Biochemistry, Genetics and Molecular Biology › Molecular Biology

RNA modifications and cancer

Works Count: 98947

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Description

This cluster of papers explores the diverse landscape of RNA methylation, with a focus on m6A modification, its impact on gene expression, ribosome biogenesis, and its role in cancer progression. The research covers various aspects such as m6A-seq, tRNA fragments, YTHDF proteins, and the involvement of methyltransferases in mRNA modification.

Keywords

m6A-seq; RNA methylation; mRNA modification; epitranscriptome; ribosome biogenesis; tRNA fragments; YTHDF proteins; cancer progression; methyltransferases; gene expression regulation

Laboratory techniques in biochemistry and molecular biology

1973-12-01

T. S. Work , E Work

N6-methyladenosine Modulates Messenger RNA Translation Efficiency

2015-06-01

Xiao Wang , Boxuan Zhao , Ian A. Roundtree +7 more

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Prescribing Personalized Nutrition for Cardiovascular Health: Are We Ready?

2014-01-01

Shanil Juma , Victorine Imrhan , Parakat Vijayagopal +1 more

Coronary artery disease (CAD) is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data … Coronary artery disease (CAD) is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data from the International HapMap Project and the development of dense genotyping chips have enabled us to perform genome-wide association studies (GWAS) on a large number of subjects without bias towards any particular candidate genes. In 2007, three chip-based GWAS simultaneously revealed the significant association between common variants on chromosome 9p21 and CAD. This association was replicated among other ethnic groups and also in a meta-analysis. Further investigations have detected several other candidate loci associated with CAD. The chip-based GWAS approach has identified novel and unbiased genetic determinants of CAD and these insights provide the important direction to better understand the pathogenesis of CAD and to develop new and improved preventive measures and treatments for CAD.

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N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions

2015-02-24

Nian Liu , Qing Dai , Guanqun Zheng +3 more

Complementary Sequence-Mediated Exon Circularization

2014-09-01

Xiao‐Ou Zhang , Haibin Wang , Yang Zhang +3 more

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Comprehensive genomic characterization of head and neck squamous cell carcinomas

2015-01-27

Michael S. Lawrence , Carrie Sougnez , Lee Lichtenstein +7 more

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated … The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs. The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs. Squamous cell head and neck cancer is one of the most common and deadly cancers. Despite initial responses to combinations of surgery, radiation and chemotherapy, approximately half of all tumours recur, usually within two years of initial diagnosis. Molecular markers and targeted therapies have had little impact on this disease to date. Here, The Cancer Genome Atlas team presents a detailed genome-wide overview of alterations and highlights critical genetic events of potential biological and clinical significance in head and neck squamous cell carcinomas (HNSCCs) with different human papillomavirus status. Mutational profiles reveal distinct subgroups of HNSCCs. Mutations in EGFR, FGFRs, PIK3CA and cyclin-dependent kinases represent candidate targets for therapeutic intervention in the majority of HNSCCs.

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N6-methyladenosine-dependent regulation of messenger RNA stability

2013-11-26

Xiao Wang , Zhike Lu , Adrian Gomez-Nguyen +7 more

Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras

2001-12-15

Erica L. Jackson , Nicholas A. Willis , Kim L. Mercer +5 more

Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. … Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras . Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.

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Tetrahymena Histone Acetyltransferase A: A Homolog to Yeast Gcn5p Linking Histone Acetylation to Gene Activation

1996-03-01

James E. Brownell , Zhou Jian-xin , Tamara A. Ranalli +4 more

We report the cloning of a transcription-associated histone acetyltransferase type A(HAT A). This Tetrahymena enzyme is strikingly homologous to the yeast protein Gcn5, a putative transcriptional adaptor, and we demonstrate … We report the cloning of a transcription-associated histone acetyltransferase type A(HAT A). This Tetrahymena enzyme is strikingly homologous to the yeast protein Gcn5, a putative transcriptional adaptor, and we demonstrate that recombinant Gcn5p possesses HAT activity. Both the ciliate enzyme and Gcn5p contain potential active site residues found in other acetyltransferases and a highly conserved bromodomain. The presence of this domain in nuclear A-type HATs, but not in cytoplasmic B-type HATs, suggests a mechanism whereby HAT A is directed to chromatin to facilitate transcriptional activation. These findings shed light on the biochemical function of the evolutionarily conserved Gcn5p-Ada complex, directly linking histone acetylation to gene activation, and indicate that histone acetylation is a targeted phenomenon.

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Regulation of microRNA biogenesis

2014-07-16

Minju Ha , V. Narry Kim

Cancer genes and the pathways they control

2004-07-30

Bert Vogelstein , Kenneth W. Kinzler

A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation

2013-12-06

Jianzhao Liu , Yanan Yue , Dali Han +7 more

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Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA

2005-08-01

Katalin Karikó , Michael Buckstein , Houping Ni +1 more

The tRNAscan-SE, snoscan and snoGPS web servers for the detection of tRNAs and snoRNAs

2005-06-26

Peter Schattner , A. N. Brooks , T. M. Lowe

Transfer RNAs (tRNAs) and small nucleolar RNAs (snoRNAs) are two of the largest classes of non-protein-coding RNAs. Conventional gene finders that detect protein-coding genes do not find tRNA and snoRNA … Transfer RNAs (tRNAs) and small nucleolar RNAs (snoRNAs) are two of the largest classes of non-protein-coding RNAs. Conventional gene finders that detect protein-coding genes do not find tRNA and snoRNA genes because they lack the codon structure and statistical signatures of protein-coding genes. Previously, we developed tRNAscan-SE, snoscan and snoGPS for the detection of tRNAs, methylation-guide snoRNAs and pseudouridylation-guide snoRNAs, respectively. tRNAscan-SE is routinely applied to completed genomes, resulting in the identification of thousands of tRNA genes. Snoscan has successfully detected methylation-guide snoRNAs in a variety of eukaryotes and archaea, and snoGPS has identified novel pseudouridylation-guide snoRNAs in yeast and mammals. Although these programs have been quite successful at RNA gene detection, their use has been limited by the need to install and configure the software packages on UNIX workstations. Here, we describe online implementations of these RNA detection tools that make these programs accessible to a wider range of research biologists. The tRNAscan-SE, snoscan and snoGPS servers are available at http://lowelab.ucsc.edu/tRNAscan-SE/ , http://lowelab.ucsc.edu/snoscan/ and http://lowelab.ucsc.edu/snoGPS/ , respectively.

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A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction

2007-05-04

Anna Helgadóttir , Guðmar Þorleifsson , Andrei Manolescu +7 more

The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. … The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.

The economics of ribosome biosynthesis in yeast

1999-11-01

Jonathan R. Warner

RNA sequencing: advances, challenges and opportunities

2010-12-30

Fatih Ozsolak , Patrice M. Milos

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Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq

2012-04-27

Dan Dominissini , Sharon Moshitch-Moshkovitz , Schraga Schwartz +7 more

N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO

2011-10-16

Guifang Jia , Ye Fu , Xu Zhao +7 more

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Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons

2012-05-17

Kate D. Meyer , Yogesh Saletore , Paul Zumbo +3 more

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Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase

2014-01-10

Xiaoli Ping , Baofa Sun , Lu Wang +7 more

The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new … The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.

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Isolation and direct complete nucleotide determination of entire genes. Characterization of a gene coding for 16S ribosomal RNA

1989-01-01

Ulrike Edwards , T. Rogall , Helmut Blöcker +2 more

Journal Article Isolation and direct complete nucleotide determination of entire genes. Characterization of a gene coding for 16S ribosomal RNA Get access Ulrike Edwards, Ulrike Edwards Institut für Medizinische Mikrobiologie, … Journal Article Isolation and direct complete nucleotide determination of entire genes. Characterization of a gene coding for 16S ribosomal RNA Get access Ulrike Edwards, Ulrike Edwards Institut für Medizinische Mikrobiologie, Medizinische Hochschule HannoverKonstanty-Gutschow-Strasse 8, D-3000 Hannover 61 Search for other works by this author on: Oxford Academic PubMed Google Scholar Till Rogall, Till Rogall Institut für Medizinische Mikrobiologie, Medizinische Hochschule HannoverKonstanty-Gutschow-Strasse 8, D-3000 Hannover 61 Search for other works by this author on: Oxford Academic PubMed Google Scholar Helmut Blöcker, Helmut Blöcker 1 GBF (Gesellschaft für Biotechnologische Forschung), Mascheroder Weg 1, D-3300 Braunschweig, FRG Search for other works by this author on: Oxford Academic PubMed Google Scholar Monica Emde, Monica Emde Institut für Medizinische Mikrobiologie, Medizinische Hochschule HannoverKonstanty-Gutschow-Strasse 8, D-3000 Hannover 61 Search for other works by this author on: Oxford Academic PubMed Google Scholar Erik C. Böttger Erik C. Böttger * Institut für Medizinische Mikrobiologie, Medizinische Hochschule HannoverKonstanty-Gutschow-Strasse 8, D-3000 Hannover 61 * To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 17, Issue 19, 11 October 1989, Pages 7843–7853, https://doi.org/10.1093/nar/17.19.7843 Published: 11 October 1989 Article history Received: 02 August 1989 Accepted: 04 September 1989 Published: 11 October 1989

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Gene expression regulation mediated through reversible m6A RNA methylation

2014-03-25

Ye Fu , Dan Dominissini , Gideon Rechavi +1 more

Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses

2001-11-13

Arindam Bhattacharjee , William G. Richards , Jane Staunton +7 more

We have generated a molecular taxonomy of lung carcinoma, the leading cause of cancer death in the United States and worldwide. Using oligonucleotide microarrays, we analyzed mRNA expression levels corresponding … We have generated a molecular taxonomy of lung carcinoma, the leading cause of cancer death in the United States and worldwide. Using oligonucleotide microarrays, we analyzed mRNA expression levels corresponding to 12,600 transcript sequences in 186 lung tumor samples, including 139 adenocarcinomas resected from the lung. Hierarchical and probabilistic clustering of expression data defined distinct subclasses of lung adenocarcinoma. Among these were tumors with high relative expression of neuroendocrine genes and of type II pneumocyte genes, respectively. Retrospective analysis revealed a less favorable outcome for the adenocarcinomas with neuroendocrine gene expression. The diagnostic potential of expression profiling is emphasized by its ability to discriminate primary lung adenocarcinomas from metastases of extra-pulmonary origin. These results suggest that integration of expression profile data with clinical parameters could aid in diagnosis of lung cancer patients.

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TIGR Gene Indices clustering tools (TGICL): a software system for fast clustering of large EST datasets

2003-03-21

Geo Pertea , Xiaoqiu Huang , Liang Feng +7 more

TGICL is a pipeline for analysis of large Expressed Sequence Tags (EST) and mRNA databases in which the sequences are first clustered based on pairwise sequence similarity, and then assembled … TGICL is a pipeline for analysis of large Expressed Sequence Tags (EST) and mRNA databases in which the sequences are first clustered based on pairwise sequence similarity, and then assembled by individual clusters (optionally with quality values) to produce longer, more complete consensus sequences. The system can run on multi-CPU architectures including SMP and PVM.

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Gene ontology analysis for RNA-seq: accounting for selection bias

2010-02-04

Matthew D. Young , Matthew J. Wakefield , Gordon K. Smyth +1 more

Abstract We present GOseq, an application for performing Gene Ontology (GO) analysis on RNA-seq data. GO analysis is widely used to reduce complexity and highlight biological processes in genome-wide expression … Abstract We present GOseq, an application for performing Gene Ontology (GO) analysis on RNA-seq data. GO analysis is widely used to reduce complexity and highlight biological processes in genome-wide expression studies, but standard methods give biased results on RNA-seq data due to over-detection of differential expression for long and highly expressed transcripts. Application of GOseq to a prostate cancer data set shows that GOseq dramatically changes the results, highlighting categories more consistent with the known biology.

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Biogenesis of small RNAs in animals

2009-01-23

V. Narry Kim , Jinju Han , Mikiko C. Siomi

Helix-Loop-Helix Proteins: Regulators of Transcription in Eucaryotic Organisms

2000-01-15

Mark E. Massari , Cornelis Murre

Click to increase image sizeClick to decrease image size ACKNOWLEDGMENTSWe thank the reviewers for their helpful comments and suggestions which improved the quality of the manuscript.M.E.M. is supported by a … Click to increase image sizeClick to decrease image size ACKNOWLEDGMENTSWe thank the reviewers for their helpful comments and suggestions which improved the quality of the manuscript.M.E.M. is supported by a postdoctoral Cancer Biology training grant from the National Institutes of Health. C.M. is supported by grants from the National Institutes of Health.

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MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer

2003-09-11

Ping Ji , Sven Diederichs , Wenbing Wang +7 more

ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility

2012-11-21

Guanqun Zheng , John Arne Dahl , Yamei Niu +7 more

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Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics

2013-12-06

Linn Fagerberg , Björn M. Hallström , Per Oksvold +7 more

Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biology and disease. Here, we used a quantitative … Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biology and disease. Here, we used a quantitative transcriptomics analysis (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this analysis with antibody-based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to ∼80% of the human protein-coding genes with access to the primary data for both the RNA and the protein analysis on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the molecular constituents of the human body.

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MicroRNA genes are transcribed by RNA polymerase II

2004-09-16

Yoontae Lee , Minju Kim , Jinju Han +4 more

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5′ UTR m6A Promotes Cap-Independent Translation

2015-10-25

Kate D. Meyer , Deepak P. Patil , Jun Zhou +6 more

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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

2014-12-05

Michael I. Love , Wolfgang Huber , Simon Anders

In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. … In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html .

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Nuclear m 6 A Reader YTHDC1 Regulates mRNA Splicing

2016-02-01

Wen Xiao , Samir Adhikari , Ujwal Dahal +7 more

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Post-transcriptional gene regulation by mRNA modifications

2016-11-03

Boxuan Zhao , Ian A. Roundtree , Chuan He

Extensive translation of circular RNAs driven by N6-methyladenosine

2017-03-10

Yun Yang , Xiaojuan Fan , Miaowei Mao +7 more

Extensive pre-mRNA back-splicing generates numerous circular RNAs (circRNAs) in human transcriptome. However, the biological functions of these circRNAs remain largely unclear. Here we report that N6-methyladenosine (m6A), the most abundant … Extensive pre-mRNA back-splicing generates numerous circular RNAs (circRNAs) in human transcriptome. However, the biological functions of these circRNAs remain largely unclear. Here we report that N6-methyladenosine (m6A), the most abundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs in human cells. We discover that consensus m6A motifs are enriched in circRNAs and a single m6A site is sufficient to drive translation initiation. This m6A-driven translation requires initiation factor eIF4G2 and m6A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO, and upregulated upon heat shock. Further analyses through polysome profiling, computational prediction and mass spectrometry reveal that m6A-driven translation of circRNAs is widespread, with hundreds of endogenous circRNAs having translation potential. Our study expands the coding landscape of human transcriptome, and suggests a role of circRNA-derived proteins in cellular responses to environmental stress.

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Dynamic RNA Modifications in Gene Expression Regulation

2017-06-01

Ian A. Roundtree , Molly Evans , Tao Pan +1 more

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Defining a Cancer Dependency Map

2017-07-01

Aviad Tsherniak , Francisca Vázquez , Phil Montgomery +7 more

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Non-coding RNA networks in cancer

2017-11-24

Eleni Anastasiadou , Leni S. Jacob , Frank J. Slack

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Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation

2018-02-15

Huilin Huang , Hengyou Weng , Wenju Sun +7 more

GENCODE reference annotation for the human and mouse genomes

2018-10-08

Adam Frankish , Mark Diekhans , Anne-Maud Ferreira +7 more

The accurate identification and description of the genes in the human and mouse genomes is a fundamental requirement for high quality analysis of data informing both genome biology and clinical … The accurate identification and description of the genes in the human and mouse genomes is a fundamental requirement for high quality analysis of data informing both genome biology and clinical genomics. Over the last 15 years, the GENCODE consortium has been producing reference quality gene annotations to provide this foundational resource. The GENCODE consortium includes both experimental and computational biology groups who work together to improve and extend the GENCODE gene annotation. Specifically, we generate primary data, create bioinformatics tools and provide analysis to support the work of expert manual gene annotators and automated gene annotation pipelines. In addition, manual and computational annotation workflows use any and all publicly available data and analysis, along with the research literature to identify and characterise gene loci to the highest standard. GENCODE gene annotations are accessible via the Ensembl and UCSC Genome Browsers, the Ensembl FTP site, Ensembl Biomart, Ensembl Perl and REST APIs as well as https://www.gencodegenes.org.

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MODOMICS: a database of RNA modification pathways. 2017 update

2017-10-18

Pietro Boccaletto , Magdalena A. Machnicka , Elżbieta Purta +7 more

MODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and … MODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. In the current database version, we included the following new features and data: extended mass spectrometry and liquid chromatography data for modified nucleosides; links between human tRNA sequences and MINTbase - a framework for the interactive exploration of mitochondrial and nuclear tRNA fragments; new, machine-friendly system of unified abbreviations for modified nucleoside names; sets of modified tRNA sequences for two bacterial species, updated collection of mammalian tRNA modifications, 19 newly identified modified ribonucleosides and 66 functionally characterized proteins involved in RNA modification. Data from MODOMICS have been linked to the RNAcentral database of RNA sequences. MODOMICS is available at http://modomics.genesilico.pl.

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GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis

2019-05-10

Zefang Tang , Boxi Kang , Chenwei Li +2 more

Abstract Introduced in 2017, the GEPIA (Gene Expression Profiling Interactive Analysis) web server has been a valuable and highly cited resource for gene expression analysis based on tumor and normal … Abstract Introduced in 2017, the GEPIA (Gene Expression Profiling Interactive Analysis) web server has been a valuable and highly cited resource for gene expression analysis based on tumor and normal samples from the TCGA and the GTEx databases. Here, we present GEPIA2, an updated and enhanced version to provide insights with higher resolution and more functionalities. Featuring 198 619 isoforms and 84 cancer subtypes, GEPIA2 has extended gene expression quantification from the gene level to the transcript level, and supports analysis of a specific cancer subtype, and comparison between subtypes. In addition, GEPIA2 has adopted new analysis techniques of gene signature quantification inspired by single-cell sequencing studies, and provides customized analysis where users can upload their own RNA-seq data and compare them with TCGA and GTEx samples. We also offer an API for batch process and easy retrieval of the analysis results. The updated web server is publicly accessible at http://gepia2.cancer-pku.cn/.

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RNA sequencing: the teenage years

2019-07-24

Rory Stark , Marta Grzelak , James Hadfield

Reading, writing and erasing mRNA methylation

2019-09-13

Sara Zaccara , Ryan J. Ries , Samie R. Jaffrey

JASPAR 2020: update of the open-access database of transcription factor binding profiles

2019-10-16

Oriol Fornés , Jaime A. Castro-Mondragón , Aziz Khan +7 more

Abstract JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In … Abstract JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). These new profiles represent an 18% expansion compared to the previous release. JASPAR 2020 comes with a novel collection of unvalidated TF-binding profiles for which our curators did not find orthogonal supporting evidence in the literature. This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. Moreover, we created a Q&A forum to ease the communication between the user community and JASPAR curators. Finally, we updated the genomic tracks, inference tool, and TF-binding profile similarity clusters. All the data is available through the JASPAR website, its associated RESTful API, and through the JASPAR2020 R/Bioconductor package.

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The Architecture of SARS-CoV-2 Transcriptome

2020-04-23

Dong-Wan Kim , Joo-Yeon Lee , Jeong-Sun Yang +3 more

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UniProt: a worldwide hub of protein knowledge

2018-10-18

The UniProt Knowledgebase is a collection of sequences and annotations for over 120 million proteins across all branches of life. Detailed annotations extracted from the literature by expert curators have … The UniProt Knowledgebase is a collection of sequences and annotations for over 120 million proteins across all branches of life. Detailed annotations extracted from the literature by expert curators have been collected for over half a million of these proteins. These annotations are supplemented by annotations provided by rule based automated systems, and those imported from other resources. In this article we describe significant updates that we have made over the last 2 years to the resource. We have greatly expanded the number of Reference Proteomes that we provide and in particular we have focussed on improving the number of viral Reference Proteomes. The UniProt website has been augmented with new data visualizations for the subcellular localization of proteins as well as their structure and interactions. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/.

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Max: A Helix-Loop-Helix Zipper Protein That Forms a Sequence-Specific DNA-Binding Complex with Myc

1991-03-08

Elizabeth M. Blackwood , Robert N. Eisenman

The myc protooncogene family has been implicated in cell proliferation, differentiation, and neoplasia, but its mechanism of function at the molecular level is unknown. The carboxyl terminus of Myc family … The myc protooncogene family has been implicated in cell proliferation, differentiation, and neoplasia, but its mechanism of function at the molecular level is unknown. The carboxyl terminus of Myc family proteins contains a basic region helix-loop-helix leucine zipper motif (bHLH-Zip), which has DNA-binding activity and has been predicted to mediate protein-protein interactions. The bHLH-Zip region of c-Myc was used to screen a complementary DNA (cDNA) expression library, and a bHLH-Zip protein, termed Max, was identified. Max specifically associated with c-Myc, N-Myc, and L-Myc proteins, but not with a number of other bHLH, bZip, or bHLH-Zip proteins. The interaction between Max and c-Myc was dependent on the integrity of the c-Myc HLH-Zip domain, but not on the basic region or other sequences outside the domain. Furthermore, the Myc-Max complex bound to DNA in a sequence-specific manner under conditions where neither Max nor Myc exhibited appreciable binding. The DNA-binding activity of the complex was dependent on both the dimerization domain and the basic region of c-Myc. These results suggest that Myc family proteins undergo a restricted set of interactions in the cell and may belong to the more general class of eukaryotic DNA-binding transcription factors.

Exploring the m5C epitranscriptome of mRNAs in breast cancer cells through genome engineering and long-read sequencing approaches

2025-06-25

Konstantina Athanasopoulou , Panagiotis G. Adamopoulos , Panagiotis Tsiakanikas +1 more | Functional & Integrative Genomics

Abstract Epitranscriptomics has emerged as a rapidly evolving field that focused on studying post-transcriptional RNA modifications and their role in spatiotemporal regulation of gene expression. N6-methyladenosine (m 6 A) and … Abstract Epitranscriptomics has emerged as a rapidly evolving field that focused on studying post-transcriptional RNA modifications and their role in spatiotemporal regulation of gene expression. N6-methyladenosine (m 6 A) and 5-methylcytosine (m 5 C) represent the most extensively studied modifications on mRNAs. These reversible modifications, mediated by ‘writer,’ ‘eraser,’ and ‘reader’ proteins, dynamically fine-tune mRNA stability, splicing, and translation. Growing evidence links their dysregulation to pathological states, including cancer progression and metastasis, where their aberrant deposition on oncogenes or tumor suppressors alters cellular signaling and therapeutic responses. In the current study, we present a detailed analysis of the m 5 C epitranscriptomic landscape across distinct breast cancer molecular subtypes. Using CRISPR/Cas9, we confirm NSUN2 as a key m 5 C writer in human mRNAs. NSUN2 loss was validated by targeted sequencing and Western blotting. Furthermore, we demonstrate the regulatory effects of NSUN2 on its canonical mRNA targets, revealing its critical role in maintaining proper gene expression networks. Our findings strongly suggest that additional m 5 C writers contribute to m 5 C methylation machinery. Additionally, we assessed the functional impact of NSUN2 depletion on mRNAs harboring m 5 C sites using mRNA stability assays. Furthermore, our analysis revealed distinct m 5 C methylation patterns among breast cancer subtypes, highlighting unique m 5 C signatures associated with the disease. Notably, we identified specific hypomethylated and hypermethylated m 5 C sites in each breast cancer cell line, representing a universal m 5 C methylation signature for breast cancer. Our study constitutes the first comprehensive m 5 C epitranscriptomic atlas in human breast cancer and paves the way for future research aimed at developing targeted therapeutic interventions that leverage the m 5 C methylation landscape.

AIMP3 maintains cardiac homeostasis by regulating the editing activity of methionyl-tRNA synthetase

2025-06-25

Anindhya Sundar Das , Charles P. Rabolli , Colton R. Martens +7 more | Nature Cardiovascular Research

Structure of fungal tRNA ligase Trl1 with RNA reveals conserved substrate-binding principles

2025-06-25

Sandra Köhler , Jürgen Kopp , S. Maiti +2 more | Nature Structural & Molecular Biology

Role of zinc finger protein 71 in hepatocellular carcinoma: Methodological concerns, clinical relevance, and future directions

2025-06-25

Arunkumar Krishnan , Diptasree Mukherjee | World Journal of Hepatology

A recent study by Qin et al emphasized the potential of zinc finger protein 71 (ZNF71) as a promising biomarker for hepatocellular carcinoma (HCC). The authors offered valuable insights into … A recent study by Qin et al emphasized the potential of zinc finger protein 71 (ZNF71) as a promising biomarker for hepatocellular carcinoma (HCC). The authors offered valuable insights into the relationship between ZNF71 and various clinical and pathological stages of HCC. However, several limitations are required to be addressed to improve the findings. These limitations include concerns regarding patient selection, the generalizability of the results, and the necessity for functional validation to establish ZNF71’s specific role in the progression of HCC. Furthermore, statistical issues related to multiple comparisons, confounding variables, and the inherent heterogeneity of high-throughput datasets warrant careful consideration. Future research should focus on multi-institutional cohorts, utilize in vivo models, and compare ZNF71 with established biomarkers to strengthen the clinical relevance of ZNF71.

RNA codon expansion via programmable pseudouridine editing and decoding

2025-06-25

Jiangle Liu , Xueqing Yan , Hao Wu +7 more | Nature

Crystal structures of free-state tRNALeu reveal conformational flexibility of Type-II tRNAs

2025-06-25

Gyuhyeok Cho , Jaehun Yoo , Kihong Shin +3 more | RNA

Transfer RNAs (tRNAs) are classified into Type-I and Type-II based on the length of their variable loops, with Type-II characterized by an extended variable loop. While structures of Type-I tRNAs … Transfer RNAs (tRNAs) are classified into Type-I and Type-II based on the length of their variable loops, with Type-II characterized by an extended variable loop. While structures of Type-I tRNAs have been well-documented, standalone structures of Type-II tRNAs have not been reported. Here, we present the first crystal structures of two free-state Type-II tRNAs, specifically tRNALeu from Bacillus subtilis and Escherichia coli. Our structures reveal that the B. subtilis tRNALeu anticodon stem-loop (ASL) retains its canonical conformation. The variable loops in both structures are well-defined, displaying a distinctive tetranucleotide loop conformation. Comparisons with Type-I tRNA and biomolecule-bound tRNAs highlight the flexibility of the ASL, variable loop, and terminal CCA residues in Type-II tRNAs, suggesting that this structural plasticity is crucial for their biological interactions and function. These findings provide new insights into the structural dynamics and functional roles of Type-II tRNAs.

S-adenosylmethionine metabolism buffering is regulated by a decrease in glycine N-methyltransferase via the nuclear ubiquitin–proteasome system

2025-06-24

Soshiro Kashio , Masayuki Miura | Proceedings of the National Academy of Sciences

Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption … Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood. In this study, we focused on the stability of SAM levels in the fat body (FB) of Drosophila, which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient deprivation. We found that glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin-proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. The inhibition of Gnmt level reduction by suppression of the nuclear UPS causes starvation tolerance. Thus, the regulation of Gnmt levels through nuclear UPS-mediated reduction helps maintain SAM levels under SAM shortage conditions.

GAGging cancer cell ferroptosis

2025-06-24

Annalisa M. VanHook | Science Signaling

Glycosaminoglycans enable cancer cells to take up antiferroptotic lipoproteins. Glycosaminoglycans enable cancer cells to take up antiferroptotic lipoproteins.

Integrated functional genomics-identified DEAF1 in oxidative stress and hepatocellular carcinoma development

2025-06-24

Linying Huang , Xinyuan Yu , Ziqi Zhang +4 more | Carcinogenesis

Abstract Hepatocellular carcinoma (HCC) is the third most common cause of death for cancer patients globally, with the overall 5-year survival rate of only 16%. The molecular mechanisms leading to … Abstract Hepatocellular carcinoma (HCC) is the third most common cause of death for cancer patients globally, with the overall 5-year survival rate of only 16%. The molecular mechanisms leading to malignant progression of HCC patients remain largely unclear. Hepatocyte nuclear factor 4α (HNF4α) functions as a tumor suppressive transcription factor (TF) in HCC. In this study, we aimed to identify functional HCC susceptibility single nucleotide polymorphisms (SNPs) in HNF4α-binding sites throughout the human genome. We identified 1,274 HNF4α-binding site polymorphisms via a genome-wide screening using TUIFGA (The Updated Integrative Functional Genomics Approach) which we previously developed to recognize cancer susceptibility SNPs within genome-wide TF-binding sites. Among these SNPs, the DEAF1 rs11246280 SNP was significantly associated with HBV-related HCC susceptibility in several case-control studies. Importantly, the rs11246280 SNP could interrupt HNF4α-binding to the DEAF1 promoter and enhance DEAF1 expression. Oncogenic TF DEAF1 binds to the SLC38A3 promoter, elevates glutamine transporter SLC38A3 expression, enhances influx of glutamine and GSH production, leads to reduced ROS levels in cells and, thereby, promotes HCC progression. Our findings highlighted the role of DEAF1 during HCC development via maintaining redox balance, which sheds light on the development of novel cancer therapeutics.

Molecular insights into glioblastoma progression: role of CHCHD2P9 in tumor heterogeneity and prognosis

2025-06-24

Yanyu Ding , Lizhi Xiao , Xiaoling Zhou +7 more | Frontiers in Immunology

Background Gliomas are highly aggressive, life-threatening tumors with poor prognosis, and remain a leading cause of mortality among brain cancers. Although the role of mitochondrial proteins in cancer has garnered … Background Gliomas are highly aggressive, life-threatening tumors with poor prognosis, and remain a leading cause of mortality among brain cancers. Although the role of mitochondrial proteins in cancer has garnered increasing attention, their specific functions in the nervous system, particularly in gliomas, remain poorly understood. Methods We integrated single-cell RNA sequencing with cellular assays and flow cytometry to investigate the molecular characteristics and cellular interactions within glioblastoma subpopulations during tumor progression. Results Single-cell RNA sequencing revealed several differentially expressed genes (DEGs) within glioblastoma subpopulations. Trajectory analysis identified CHCHD2P9 as a pivotal marker for the terminal subpopulation. Moreover, elevated expression of CHCHD2P9 was found to correlate with poorer clinical outcomes. Subsequent cellular experiments further explored the underlying mechanisms driving these observations. Conclusions CHCHD2P9 is significantly overexpressed in glioma patients, and its differential expression plays a crucial role in regulating glioma cell proliferation and migration. A CHCHD2P9-based risk model holds promise as both a prognostic biomarker and a potential therapeutic target, providing novel insights into the pathogenesis of gliomas and opening avenues for personalized treatment strategies.

Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC)-stabilized lncRNA small nucleolar RNA host gene 15 (Snhg15) modulates hematopoietic injury induced by γ-ray irradiation via m6A modification

2025-06-24

Shuqin Zhang , Yajia Cheng , Yujia Gao +6 more | Molecular Biomedicine

Abstract With advancements in radiotherapy technologies, the detrimental effects of ionizing radiation on biological systems, particularly the hematopoietic system, have caused significant concern. N 6 -methyladenosine (m 6 A), the … Abstract With advancements in radiotherapy technologies, the detrimental effects of ionizing radiation on biological systems, particularly the hematopoietic system, have caused significant concern. N 6 -methyladenosine (m 6 A), the most pervasive representative of post-transcriptional modifications, plays critical roles in diverse biological events. Non-coding RNA comprises the vast majority of the human genome. This study aimed to explore the role of long non-coding RNA (lncRNA) m 6 A modification in γ-ray irradiation-induced hematopoietic injury. By using mouse models, it was found that γ-radiation rapidly damaged hematopoietic bone marrow cells (BMCs), triggering apoptosis, oxidative stress and DNA damage, along with up-regulation of m 6 A Reader proteins. We revealed the time-conditioned landscape of lncRNA m 6 A methylome of BMCs in the short term after radiation and found that a dynamic “change-then-recover” trend involved. LncRNA Snhg15 was identified as a key regulator through integration analysis of the methylome and transcriptome data. Its m 6 A modification was closely related to progression of radiation injury in BMCs. Further research demonstrated that the novel m 6 A Reader LRPPRC could interact with the modification site of Snhg15 , stabilize Snhg15 and promote its expression, thereby exacerbating radiation-induced injury to BMCs both in vitro and in vivo. Knockdown of Lrpprc or Snhg15 could alleviate the radiation injury to the hematopoietic system. Additionally, the LRPPRC- Snhg15 axis was involved in the radio-protective efficacy of gut microbiota-derived valeric acid. These findings uncover a novel mechanism by which m 6 A-modified lncRNA Snhg15 is stabilized by LRPPRC modulates γ-irradiation-induced hematopoietic injury, providing potential therapeutic targets for the prevention and treatment of radiation injuries.

Sex-Dependent Relationships Between PFAS and Placental Transcriptomics Identified by Weighted Gene Co-Expression Analysis

2025-06-24

Cynthia Perez , Kyle A. Campbell , Dana Boyd Barr +5 more

Background Per– and polyfluoroalkyl substances (PFAS) are environmental toxicants associated with adverse neonatal outcomes. The exact mechanisms by which PFAS impairs neonatal health are undefined, but the placenta is a … Background Per– and polyfluoroalkyl substances (PFAS) are environmental toxicants associated with adverse neonatal outcomes. The exact mechanisms by which PFAS impairs neonatal health are undefined, but the placenta is a likely target. Objective We applied a systems biology approach to identify placental RNA co-expression modules (gene sets) associated with PFAS exposure and birth weight. Methods Placental tissue samples (n = 147) from the GLOWING study underwent RNA-sequencing, and PFAS concentrations were quantified using liquid chromatography-tandem mass spectrometry. We constructed a weighted gene co-expression network using Spearman correlations across 15,028 transcripts, identifying 20 gene modules. Linear regression models were used to examine associations between PFAS and module eigengenes, adjusting for potential confounders. Effect modification by fetal sex was also tested. Results One module showed a negative association with perfluorononanoic acid (PFNA; β = – 0.012, q = 0.009). This association was sex-specific, with the sexes exhibiting varied PFAS associations but similar directional effects. Genes within the PFNA-associated module were involved in histone modification (q ≤ 0.05) and were enriched for targets of the Vitamin D Receptor (VDR), a transcription factor previously linked to PFAS. Discussion Our research indicates that prenatal exposure to PFNA influences placental gene expression differently based on sex, which may affect insulin growth factor signaling and histone modification. The presence of VDR in this module and the transcription enrichment analysis align with previous findings regarding PFAS and VDR interactions. This module related to PFNA could shed light on the molecular pathways connecting PFAS exposure to health outcomes in neonates.

Development of tRNA-based biomarkers for breast cancer: Insight from machine learning

2025-06-24

Quan Yuan , J. Ye , Yu Hao +2 more | Archives of Medical Science

Introduction Breast cancer (BC) is one of the most frequent cancers in women globally. Research on tRNA-related biomarkers for predicting BC survival remains notably lacking. In this study, bioinformatics analysis … Introduction Breast cancer (BC) is one of the most frequent cancers in women globally. Research on tRNA-related biomarkers for predicting BC survival remains notably lacking. In this study, bioinformatics analysis was utilized to identify tRNA-related gene targets. Material and methods We obtained closely related mRNAs by screening BC prognosis-associated tRNAs from the OncotRF database. Next, we selected prognostically important mRNAs further using the Bruta algorithm. We developed a risk model based on these significant genes by using a variety of machine learning techniques and validated the expression with experiment. Data from the TCGA, GEO, and IMvigor210 datasets were used to validate the predictive efficacy of the t-mRNA characteristics. We also obtained the single-cell RNA sequencing (scRNA-Seq) data from the TISCH2 database and the RNA-Seq data from the UCSC Xena database for pan-cancer analysis. Results We created a prognostic model with 12 t-mRNAs associated with BC. Strong predictive performance of this model was demonstrated by nomogram, ROC and survival analyses. Functional enrichment analysis revealed differences between the low-risk and high-risk groups in immunological-related biological processes. The high-risk group showed reduced immunotherapy efficiency and greater M2 macrophage infiltration, according to the analysis of immune infiltration and immunotherapy responsiveness. Furthermore, the pan-cancer investigation revealed that high-risk tumors typically exhibit more aggressive features. We also found the express difference of model genes between normal and cancer cells. Conclusions We created an t-mRNA feature that may accurately predict the prognosis of BC patients and promote the development of precision medicine for cancer.

How to spy on condensates

2025-06-24

Vivien Marx | Nature Methods

Publisher Correction: Transposable element methylation tracks age

2025-06-24

Bernadette Hotzi , Tibor Vellai | Nature Aging

Genetic Association and Functional Validation of ZFP36L2 in Non-Syndromic Orofacial Cleft Subtypes

2025-06-24

Jielin Sun | International Journal of Oral and Maxillofacial Surgery

De novo assembly of RNA m6A modification factors into viral genome-associated nuclear bodies drives HCMV RNA accumulation

2025-06-24

Rebecca Grande , Chia-Ching Lin , Michael Cammer +7 more | Cell Reports

Gut commensal bacteria-derived methionine is required for host reproduction by modulating RNA m6A methylation of the insulin receptor

2025-06-24

Qiuyuan Zhang , ZhuRong Deng , Xiaoxue Li +7 more | Cell Reports

Differential Transcriptional Activity of ΔNp63β Is Encoded by an Isoform-Specific C-Terminus

2025-06-23

Abby A. McCann , Morgan A. Sammons | Molecular and Cellular Biology

p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role … p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role in the progression of epithelial-associated cancers. Unraveling the specific biochemical mechanisms underlying these phenotypes is made challenging by the presence of multiple p63 isoforms and their shared and unique contributions to development and disease. Here, we explore the function of the p63 isoforms ΔNp63ɑ and ΔNp63β to determine the contribution of C-terminal splice variants on known and unique molecular and biochemical activities. Using RNA-seq and ChIP-seq on isoform-specific cell lines, we show that ΔNp63β regulates both canonical ΔNp63ɑ targets and a unique set of genes with varying biological functions. We demonstrate that most genomic binding sites are shared, however the enhancer-associated histone modification H3K27ac is highly enriched at ΔNp63β binding sites relative to ΔNp63ɑ. An array of ΔNp63β C-terminal mutants demonstrates the importance of isoform-specific C-terminal domains in regulating these unique activities. Our results provide novel insight into differential activities of p63 C-terminal isoforms and suggest future directions for dissecting the functional relevance of these and other transcription factor isoforms in development and disease.

Integrated multi-omics analysis of UL16-binding protein 2 as a prognostic and immunotherapy biomarker for colorectal cancer

2025-06-23

Xianjun Qu , Yong Xu , Ruimin Wu +4 more | Functional & Integrative Genomics

Systematic pan-cancer analysis identifies PKNOX1 as a potential prognostic and immunological biomarker and its functional validation

2025-06-23

Kan Liu , Yongkang Xu , Mao Ye +3 more | Frontiers in Immunology

Background PBX/knotted1 homeobox 1 (PKNOX1), also known as PREP1, is a homeodomain transcription factor that has been reported to be involved in the progression of gastric adenocarcinoma and non-small cell … Background PBX/knotted1 homeobox 1 (PKNOX1), also known as PREP1, is a homeodomain transcription factor that has been reported to be involved in the progression of gastric adenocarcinoma and non-small cell lung cancer. However, its expression, clinical significance, and biological function in various human cancers have not been studied in depth, and its role and specific molecular mechanism in the occurrence and development of cancer remain unclear. Its potential as a cancer prognostic marker and therapeutic target has not yet been explored. Methods The TCGA and GTEx databases were used to evaluate the differential expression of PKNOX1 pan-cancer, and PKNOX1 gene mutation information was obtained from the cBioPortal and GSCALite platforms. Cox regression and Kaplan-Meier analyses were used to evaluate the value of PKNOX1 in pan-cancer prognosis. The correlations between PKNOX1 expression and the expression of DNA methylation-related genes, immune-related genes, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed using Spearman correlation. The correlations between PKNOX1 expression and MDSC immune infiltration and immune cells were analyzed using the TIDE algorithm and the ESTIMATE algorithm. PKNOX1 -interacting proteins and expression-related genes were analysed via the STRING and TIMER 2.0 platforms, and the functions of PKNOX1 in tumors and the cell pathways involved were predicted via KEGG enrichment analysis. In addition, the differential expression and function of PKNOX1 in HCC and breast cancer were explored via Western blotting and proliferation and migration-related experiments. Results PKNOX1 is significantly highly expressed in most tumor types and is significantly associated with poor patient prognosis and increased clinicopathological stage. Tumor gene mutations and DNA methylation may explain the abnormal expression of PKNOX1. In most tumors, PKNOX1 expression was significantly correlated with MDSC immune infiltration and immune cells, methylation-related genes, immune-related genes, the TMB and MSI. The enriched KEGG pathways indicated that PKNOX1 is involved in cancer-promoting processes such as cell-cell adhesion, the cell cycle and cell proliferation and deterioration signalling pathways. In vitro experiments revealed that PKNOX1 is highly expressed in HCC and breast cancer cells and HCC tissues and promotes the growth, proliferation, migration and invasion of HCC and breast cancer cells. Conclusion PKNOX1 is a promising prognostic and immune biomarker in pan-cancer and may play an important role in HCC and breast cancer progression and metastasis.

Single-cell transcriptomic and m6A methylation analyses reveal platelet-mediated immune regulatory mechanisms in sepsis

2025-06-23

Weiwei Qian , Yuanyuan Liu , Xinyang Zhao +3 more | Frontiers in Immunology

Objective Sepsis is a systemic inflammatory response syndrome triggered by infection, characterized by high clinical heterogeneity and complex immunopathological mechanisms. Immune dysregulation plays a central role in its progression. This … Objective Sepsis is a systemic inflammatory response syndrome triggered by infection, characterized by high clinical heterogeneity and complex immunopathological mechanisms. Immune dysregulation plays a central role in its progression. This study aims to investigate the compositional changes of immune cells, characteristics of intercellular communication, and potential regulatory mechanisms of N⁶-methyladenosine (m 6 A) modification in sepsis, with a particular focus on the functional remodeling of platelets. Methods This study integrated single-cell RNA sequencing data (GSE167363 dataset) from sepsis patients with m 6 A methylation sequencing data of peripheral blood mononuclear cells (PBMCs). Through systematic analysis, we compared the differences in immune cell composition, developmental trajectories, intercellular communication, and m 6 A modifications among healthy controls, survivors, and non-survivors, and further screened for key m 6 A-regulated target genes. Results The analysis revealed that platelets gradually accumulated during the progression of sepsis, while B cells, T cells, and regulatory T cells (Tregs) exhibited a trend toward platelet-like phenotypic remodeling. Cell–cell communication analysis showed a marked decline in communication strength among immune cells as the disease worsened, particularly a significant weakening of the APP–CD74 signaling pathway between platelets and B cells, indicating impaired immune network synergy. m⁶A methylation sequencing revealed distinct remodeling of m⁶A peaks and dysregulation of related regulatory factors in non-survivors. Further integrative analysis identified RPA1 as a key m⁶A-regulated target gene, whose expression was closely associated with APP and co-regulated by multiple m 6 A-modifying factors. Conclusion This study reveals disruptions in immune cell interactions and an m 6 A-dependent mechanism of platelet functional remodeling during sepsis progression. The identification of the key target gene RPA1 offers new insights into the immunopathological mechanisms of sepsis and lays a theoretical foundation for future precision interventions and therapeutic strategies.

METTL14/YTHDF2 m6A Axis Protects Against M2 Macrophage Polarization in Endometriosis by Regulating KLF4 Stability

2025-06-23

Li Li , Xiaoyan Wang , You Wu +2 more | Applied Biochemistry and Biotechnology

A Clinical Study of Nine Patients With <scp>ReNU</scp> Syndrome

2025-06-23

Nobuhiko Okamoto , Eriko Nishi , Yuiko Hasegawa +6 more | American Journal of Medical Genetics Part A

ABSTRACT ReNU syndrome, also known as neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA), is characterized by hypotonia, global developmental delay, intellectual disability with poor or … ABSTRACT ReNU syndrome, also known as neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA), is characterized by hypotonia, global developmental delay, intellectual disability with poor or absent speech, delayed motor development, feeding difficulties, short stature, seizures, and dysmorphic features. Neuroradiological abnormalities, including ventriculomegaly, hypoplasia of the corpus callosum, and a decreased white matter volume, are observed in many individuals. Most individuals have the same highly recurrent single base insertion (n.64_65insT) in RNU4‐2 . RNU4‐2 encodes U4 small nuclear RNA, which is a critical component of the U4/U6.U5 tri‐snRNP complex of the major spliceosome. We reviewed exome sequencing and genome sequencing data from previous patients with neurodevelopmental disorders that matched the clinical features of ReNU syndrome and performed a hotspot analysis using the Sanger method. A recurrent variant in RNU4‐2 was identified in eight patients, while the rare variant, n.66A>G, was detected in one patient. Nine patients aged between 3 and 29 years all showed severe developmental delay and/or intellectual disability. Independent walking was achieved by five patients. In six patients, meaningful words had not been acquired, even after the age of 5 years. All patients showed a distinctive pattern of dysmorphic features, including hooded upper eyelids, full cheeks, a tented philtrum, and a mouth constantly slightly open with an everted lower lip vermilion. All patients had neuroradiological abnormalities. The identification of nine patients at a single institution reaffirmed that ReNU syndrome is an important cause of ID. ReNU syndrome is considered a clinically recognizable syndrome. If clinically suspected, it is reasonable to examine the 18‐base pair region using the Sanger method.

<scp>RNA</scp> Binding Protein <scp>YTHDF2</scp> Inhibits Synovial Fibroblast Inflammation and Bone Injury in Rheumatoid Arthritis by Reducing the <scp>mRNA</scp> Stability of <scp>IL</scp>‐<scp>6R</scp>

2025-06-23

Yan Zhang , Xuqing Cao , Xiaoli Ma +7 more | The Kaohsiung Journal of Medical Sciences

This study examined YTHDF2's role in modulating IL-6R signaling to regulate synovial fibroblast inflammation and bone damage in rheumatoid arthritis (RA). Synovial tissues of RA patients were collected. Human fibroblast-like … This study examined YTHDF2's role in modulating IL-6R signaling to regulate synovial fibroblast inflammation and bone damage in rheumatoid arthritis (RA). Synovial tissues of RA patients were collected. Human fibroblast-like synoviocyte (FLS), MH7A cell line, was induced with TNF-α and transfected. Cell proliferation was assessed using MTT and EdU assays; apoptosis was measured with flow cytometry, and migration and invasion were evaluated through scratch and Transwell assays. Lentiviral vectors designed to overexpress YTHDF2 or IL-6R were created to study their effects in mice with collagen-induced arthritis (CIA). Pathological changes of ankle joints in mice were observed, and TNF-α, IL-1β, and IL-6 contents were determined. MMP3 and MMP9 levels were detected by Western blot, while YTHDF2 and IL-6R were detected by RT-qPCR and Western blot. The binding relationship between YTHDF2 and IL-6R was studied. YTHDF2 in synovial tissues of RA patients was down-regulated. Elevating YTHDF2 inhibited TNF-α-induced MH7A cell proliferation, migration, invasion, and pro-inflammatory factors; Knocking down YTHDF2 showed the opposite effect. Upregulating YTHDF2 improved synovial inflammation and bone damage in CIA mice. IL-6R in synovial tissues of patients was significantly up-regulated and negatively correlated with YTHDF2 expression. YTHDF2 reduced IL-6R mRNA stability in a m6A-dependent manner. Overexpressing IL-6R impaired the anti-proliferating and anti-inflammatory effect of YTHDF2 on TNF-α-induced MH7A cells. In CIA mice, overexpression of IL-6R reversed the benefits on synovial inflammation and bone injury mediated by up-regulating YTHDF2. YTHDF2 inhibits inflammation and bone damage in RA synovial fibroblasts by reducing the mRNA stability of IL-6R.

METTL3 regulates PRRSV replication by suppressing interferon beta through autophagy-mediated IKKε degradation

2025-06-23

Yunyun Zhai , Wang Lu-cai , Lijie Lv +7 more | Journal of Virology

Methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m6A) modification of messenger RNAs plays a pivotal role in regulating innate immune responses, either promoting or combating virus replication. However, the biological function of METTL3 during … Methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m6A) modification of messenger RNAs plays a pivotal role in regulating innate immune responses, either promoting or combating virus replication. However, the biological function of METTL3 during porcine reproductive and respiratory syndrome virus (PRRSV) infection remains unclear. In this study, we found that PRRSV infection reprograms m6A modifications in cellular transcripts, enhances METTL3 expression, and alters its subcellular distribution. Intriguingly, METTL3 overexpression facilitates PRRSV replication, whereas its deficiency suppresses it, primarily through the negative regulation of type I interferon (IFN-I) production. Further investigation revealed that METTL3 interacts with and promotes the degradation of IκB kinase-ε (IKKε) during PRRSV infection. Mechanistically, METTL3-mediated m6A modification of SQSTM1 (sequestosome 1) enhances SQSTM1 messenger RNA (mRNA) expression, increasing autophagy levels. Moreover, METTL3 facilitates the formation of K63-linked ubiquitin chains on IKKε, targeting it for degradation via SQSTM1-dependent selective autophagy. Collectively, our findings unveil a novel mechanism whereby METTL3 facilitates PRRSV replication by suppressing antiviral innate immunity, thereby offering potential targets for antiviral therapy.IMPORTANCEPorcine reproductive and respiratory syndrome (PRRS), induced by the porcine reproductive and respiratory syndrome virus (PRRSV), poses a highly contagious threat to the global swine industry, leading to substantial economic losses. The genetic variability and immune evasion capabilities of PRRSV complicate the development of effective vaccines and control strategies. Thus, a comprehensive understanding of PRRSV's immune evasion mechanisms is imperative. In this study, we reveal that METTL3 plays a pivotal role in PRRSV's evasion of interferon (IFN) immunity. Specifically, METTL3 targets IKKε, inducing its autophagy degradation and subsequently inhibiting the expression of interferon beta 1 (IFNB1). Furthermore, PRRSV infection alters the N6-methyladenosine (m6A) modification of various host genes, with notable changes observed in the m6A modification and transcriptional levels of SQSTM1, which are regulated by METTL3. This regulation is crucial for SQSTM1-mediated autophagy degradation of IKKε. Our findings offer novel insights into the mechanisms underlying host protein involvement in PRRSV's immune evasion.

WDR35 Is Associated with Chemosensitivity and Prognosis in Lung Adenocarcinoma

2025-06-23

Liang Tang , Yinhui Xu , Xinmiao Zhang +5 more | Cancer Biotherapy and Radiopharmaceuticals

Background: This study investigates the expression characteristics of WD repeat domain 35 (WDR35) in lung adenocarcinoma (LUAD) and its association with chemotherapy sensitivity and prognosis. Methods: Differentially expressed genes were … Background: This study investigates the expression characteristics of WD repeat domain 35 (WDR35) in lung adenocarcinoma (LUAD) and its association with chemotherapy sensitivity and prognosis. Methods: Differentially expressed genes were analyzed in combination with Random Forest and Support Vector Machine algorithms to identify key genes associated with chemotherapy sensitivity. The expression differences of the core gene at both transcriptomic and proteomic levels were then experimentally validated using real-world LUAD samples. Drug sensitivity analysis was conducted using the Genomics of Drug Sensitivity in Cancer database to evaluate the correlation between the core gene and the IC50 values of various chemotherapeutic agents. Gene Set Enrichment Analysis (GSEA) was used to explore the potential mechanisms involved. Finally, Kaplan-Meier survival analysis and stratified analysis by tumor stage and lymph node status were performed to assess the prognostic value of the core gene. Results: WDR35 as a core gene associated with chemotherapy sensitivity and highly expressed in normal lung tissue compared with tumor tissue, which was further validated at both the qPCR and proteomic levels. Clinical correlation analysis indicated that WDR35 expression is significantly associated with tumor size, lymph node metastasis, and tumor stage. Further analysis revealed that patients with high WDR35 expression were more likely to achieve partial or complete response to initial chemotherapy. Drug sensitivity prediction analysis demonstrated that high WDR35 expression was significantly correlated with increased sensitivity to various anticancer drugs. GSEA pathway enrichment analysis suggested that WDR35 may enhance chemotherapy sensitivity by regulating stress response and metabolic pathways. Survival analysis indicated that high WDR35 expression was associated with better overall survival and disease-specific survival. Conclusions: Our study reveals that WDR35 is closely associated with chemotherapy sensitivity and prognosis in lung adenocarcinoma.

hUC-MSC-derived extracellular vesicles protect lung tissue from cigarette smoke-induced injury by upregulating the METTL3-mediated m6A modification

2025-06-23

Jun Wen , Jianwei Xu , Ying Li +4 more | AJP Cell Physiology

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), a prevalent and incurable lung disease. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) exhibit therapeutic potential … Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), a prevalent and incurable lung disease. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) exhibit therapeutic potential in treating COPD. However, the precise mechanism underlying their beneficial effects in lung epithelial cells exposed to cigarette smoke remains incompletely understood. In this study, we purified hUC-MSC-EVs and assessed their influence on viability, apoptosis, and pyroptosis in BEAS-2B human bronchial epithelial cells treated with cigarette smoke extract (CSE). Our data revealed that CSE-treated BEAS-2B cells uptake hUC-MSC-EVs, which significantly improved cell viability and suppressed apoptosis and pyroptosis. Mechanistically, hUC-MSC-EVs partially restored the decreased m6A modification, a key regulator of COPD, in CSE-treated BEAS-2B cells by upregulating the m6A writer METTL3. Depletion of METTL3 abolished the protective effect of hUC-MSC-EVs against CSE-induced damage in BEAS-2B cells. The levels of METTL3 were also positively associated with the Wnt/β-catenin pathway. Additionally, we investigated the protective effect of hUC-MSC-EVs on lung tissues in a COPD rat model, confirming the regulation of METTL3 expression and the Wnt/β-catenin pathway by hUC-MSC-EVs in vivo. These findings collectively validate the protective effect of hUC-MSC-EVs on lung epithelial cells exposed to cigarette smoke and highlight the therapeutic potential of targeting the METTL3-Wnt axis in COPD treatment.

Prognostic stratification in liver cancer using an m6A-associated non-coding RNA risk model

2025-06-23

Hongwei Liu , Canfeng Cai , Xianghui Du +3 more | Journal of Radiation Research and Applied Sciences

Exploring the potential mechanisms of m6A modification in septic acute respiratory distress syndrome: a bioinformatics analysis

2025-06-23

Shaoyang Zhang , Qinghui Fu , Zhipeng Xu +3 more | Hereditas

Acute respiratory distress syndrome (ARDS) remains a leading cause of mortality in intensive care units. The N6-methyladenosine (m6A) mRNA modification is critical in various pathological conditions, yet its role in … Acute respiratory distress syndrome (ARDS) remains a leading cause of mortality in intensive care units. The N6-methyladenosine (m6A) mRNA modification is critical in various pathological conditions, yet its role in the ARDS microenvironment, particularly at the single-cell level, remains poorly understood. Single-cell and bulk RNA-sequencing datasets were sourced from the GEO databases. Bioinformatics and experimental approaches were employed to investigate the associations between m6A regulators and hub genes in ARDS. WTAP, HNRNPA2B1, and HNRNPC exhibited extensive expression within the ARDS microenvironment. Consensus clustering analysis segregated patients with sepsis into distinct subgroups, with WTAP showing significant variation across these groups. Weighted gene co-expression network analysis (WGCNA) identified the brown module as most associated with WTAP, revealing five hub genes. Validation experiments confirmed high expression levels of WTAP and MYC in lung tissues. Functional assays further demonstrated that WTAP enhances ARDS progression. In conclusion, bioinformatics analysis and preliminary experimental data suggest that WTAP promotes ARDS onset and progression by regulating m6A methylation and facilitating immune cell infiltration.

Methylation Profile of Cell-Free DNA as a Diagnostic Marker for Myocarditis

2025-06-23

Anna V. Zykova , Svyatoslav S. Malyshkin , Eugeniy V. Mullin +1 more | Bulletin of the Russian Military Medical Academy

Studies on epigenetic modifications that could enable the tissue-specific partitioning of a general pool of circulating cell-free DNA for diagnosing myocarditis were analyzed. Despite the long history of research on … Studies on epigenetic modifications that could enable the tissue-specific partitioning of a general pool of circulating cell-free DNA for diagnosing myocarditis were analyzed. Despite the long history of research on cardiovascular disease, the actual incidence of myocarditis within the population remains unclear, as the condition is difficult to detect using conventional diagnostic methods. The advantages of screening a pool of cell-free DNA in the peripheral blood for detecting various pathologies (such as cancer, fetal aneuploidies, and transplant rejection) have been acknowledged worldwide. However, this approach is limited when analyzing the cell-free DNA derived from the reference genome. DNA methylation is one of the most crucial and well-studied mechanisms of epigenetic regulation. The aberrant methylation status of candidate genes is implicated in the development of cardiovascular diseases and may serve as a marker for assessing their progression. The methylation patterns are unique to each cell type, remain consistent among the same cell type within an individual, and are characterized by high stability. The studies reviewed identified loci associated with cardiomyocyte-specific patterns of DNA methylation. Moreover, in various diseases of the circulatory system, the same cytosine–guanine dinucleotide sites were found to be differentially methylated. This finding not only confirms the close association between DNA methylation profiles and cardiovascular diseases but also supports the hypothesis that the methylation status of specific cytosine–guanine dinucleotide sites has high diagnostic specificity for various pathologies. Thus, an analysis of cell-free DNA methylation profiles confirms its tissue-specific origin and enables the development of highly specific diagnostic approaches for myocardial disorders. Furthermore, comparing the methylation levels of identical cytosine–guanine dinucleotide sites offers promising opportunities for the development of highly specific diagnostic systems for myocarditis and other cardiovascular diseases.

Epitranscriptomic Modulation of TET2-inhibition Suppressed SARS-CoV-2 Infection and Blocked Viral N-protein in iPSC-Cardiomyocytes Screening Models

2025-06-23

Yi-Ping Yang , Chia-Hao Wang , Jun‐Ren Sun +7 more | Biomaterials Research

MitoTracer facilitates the identification of informative mitochondrial mutations for precise lineage reconstruction

2025-06-23

Xuexin Yu , Jing Hu , Yuhao Tan +3 more | PLoS Computational Biology

Mitochondrial (MT) mutations serve as natural genetic markers for inferring clonal relationships using single cell sequencing data. However, the fundamental challenge of MT mutation-based lineage tracing is automated identification of … Mitochondrial (MT) mutations serve as natural genetic markers for inferring clonal relationships using single cell sequencing data. However, the fundamental challenge of MT mutation-based lineage tracing is automated identification of informative MT mutations. Here, we introduced an open-source computational algorithm called "MitoTracer", which accurately identified clonally informative MT mutations and inferred evolutionary lineage from scRNA-seq or scATAC-seq samples. We benchmarked MitoTracer using the ground-truth experimental lineage sequencing data and demonstrated its superior performance over the existing methods measured by high sensitivity and specificity. MitoTracer is compatible with multiple single cell sequencing platforms. Its application to a cancer evolution dataset revealed the genes related to primary BRAF-inhibitor resistance from scRNA-seq data of BRAF-mutated cancer cells. Overall, our work provided a valuable tool for capturing real informative MT mutations and tracing the lineages among cells.

A pyrimidine metabolism-related gene signature for prognosis prediction and immune microenvironment description of breast cancer

2025-06-23

Han Wang , Ziling Zhou , Hanyi Zhong +5 more | Journal of Translational Medicine

Metabolic reprogramming is a hallmark in cancer. Pyrimidine metabolism (PM), a part of nucleotide metabolism, has been shown to be associated with the progression of various cancers, and the prognostic … Metabolic reprogramming is a hallmark in cancer. Pyrimidine metabolism (PM), a part of nucleotide metabolism, has been shown to be associated with the progression of various cancers, and the prognostic predictive ability of pyrimidine metabolism-related genes (PMG) in breast cancer has not been elucidated. This paper was designed to identify pyrimidine metabolism-related prognostic marker of breast cancer and potential targeted therapeutic options. The cohort in the TCGA-BRCA dataset was used for patient information, and 108 pyrimidine metabolism-related genes were identified from the MSigDB KEGG pathways. We identified PM clusters in breast cancer and established a PM risk score model based on 10 pyrimidine metabolism-related genes. The status of immune infiltration was assessed in different groups. Further we identified the relevant hub gene and analyzed its significance for breast cancer metastasis and explored patterns of combination therapy. We identified three types of PM clusters in breast cancer and clarified that PM cluster C with inferior prognosis possessed activation of tumor proliferation-associated pathways. The high-risk group in PM risk score model was found to be characterized by an immunosuppressive microenvironment. The hub gene POLR2C (RNA polymerase II subunit C) was further identified and verified as a potential prognostic marker. Furthermore, targeting POLR2C in combination with anti-PD-1 and anti-angiogenic therapies demonstrated a promising tumor suppression effect, suggesting a potential therapeutic direction. These findings provide additional insights into the link between breast cancer and PMG, offering potential strategies for breast cancer management and treatment.

ALKBH5‐Mediated M6A Demethylation of G3BP1 Attenuates Ferroptosis Via Cytoplasmic Retention of YBX1/p53 in Diabetic Myocardial Ischemia‐Reperfusion Injury

2025-06-23

Wenyuan Li , Wei Li , Yan Leng +3 more | Advanced Science

The overexpression of ALKBH5 alleviates damage to cardiomyocytes and tissues, decreases the expression of SLC7A11, and inhibits the expression of p53N/T and ferroptosis. ALKBH5 induces ferroptosis in the HH/R model … The overexpression of ALKBH5 alleviates damage to cardiomyocytes and tissues, decreases the expression of SLC7A11, and inhibits the expression of p53N/T and ferroptosis. ALKBH5 induces ferroptosis in the HH/R model by mutating the 3'-UTR of G3BP1 mRNA and m6A sites at positions 142 and 173. Mutations of sites 142 and 173 only partially affect the levels of p53N/T, SLC7A11 and ferroptosis. G3BP1, YBX1 and p53 protein can bind to each other, and p53 can inhibit the expression of SLC7A11 via nuclear binding to the promoter region of SLC7A11 mRNA. The p53 and YBX1 proteins can synergistically enter the nucleus to aggravate cell damage, while G3BP1 is expressed in the cytoplasm and inhibits p53 binding to SLC7A11 by blocking the entry of the p53 and YBX1 proteins into the nucleus. ALKBH5 promotes G3BP1 expression through m6A methylation at m6A sites 142 and 173. Subsequently, G3BP1, YBX1, and p53 interact with each other, the amount of synergistic nuclear translocation of YBX1 and p53 is reduced, and the level of p53 nuclear translocation that inhibiting SLC7A11 transcription is decreased, thereby inhibits cardiomyocyte ferroptosis and reducing myocardial tissue damage during myocardial IRI in diabetes.

Multi-Omics Integration of Lactylation- and PANoptosis-Based Signatures in Lung Adenocarcinoma: Prognostic Stratification and Immune Response

2025-06-23

Zhenhao Xu , Yisha Huang , Xiuling Yu +2 more | International Journal of Molecular Sciences

Lactylation and PANoptosis are emerging modes of tumor progression regulation; however, their interplay and effect on the prognosis for lung adenocarcinoma (LUAD) remain unclear. This research analyzed both bulk and … Lactylation and PANoptosis are emerging modes of tumor progression regulation; however, their interplay and effect on the prognosis for lung adenocarcinoma (LUAD) remain unclear. This research analyzed both bulk and single-cell transcriptomic profiles of LUAD and identified 506 potential markers related to lactylation and PANoptosis. Employing 117 machine learning approaches and 5 LUAD datasets, lactylation and PANoptosis-related signatures (LAPRS) and further predictive nomograms were constructed with 85 prognostic genes. The performance of LAPRS was validated with multifaceted validation, including Kaplan–Meier analysis, time-dependent ROC curves and comparison with 55 existing LUAD models. LAPRS enabled the stratification of LUAD patients into high- and low-risk subgroups. Through additional investigation, high-risk individuals showed elevated genomic alterations, reduced immune infiltration, and poorer immunotherapy response, while low-risk individuals showed better drug sensitivity and a higher tumor mutation burden. Further analysis via 18 models and experimental validation revealed APOL1 as a poor prognostic factor, potentially interacting with the lactylation-related gene VIM through TNF signaling. This research clarifies the mechanistic roles of lactylation and PANoptosis in LUAD and proposes APOL1 as a novel prognostic marker, offering insights for therapeutic stratification.

Fragmentation of nucleoli in senescent cancer cells is associated with increased levels of polyadenylated transcripts derived from noncoding regions of rDNA units

2025-06-23

Jana Sochorová , Emı́lie Lukášová , Eva Polanská +2 more | European Biophysics Journal

In this study, we investigated the behavior of rDNA loci in senescent MCF-7 mammary cancer cells induced by gamma irradiation. To analyze changes in nucleolar structure we used rDNA-FISH and … In this study, we investigated the behavior of rDNA loci in senescent MCF-7 mammary cancer cells induced by gamma irradiation. To analyze changes in nucleolar structure we used rDNA-FISH and immunohistochemical staining with fibrillarin and UBF transcription factor. The expression levels of rDNAs and nucleolar proteins were determined by RNA-seq of total and poly-A libraries. The cytological and molecular parameters of nucleoli were monitored throughout the 7-day interval following irradiation. Senescent cells exhibited a higher proportion of smaller nucleoli as compared to cycling cells, indicating nucleolar fragmentation. The rDNA copy number and expression of rDNA variants remained stable in cycling and senescent cells. However, the levels of polyadenylated rRNA species derived from external (5'ETS) and internal (ITS1) rDNA spacers tend to increase (c.2 fold) following irradiation. At the protein level, senescent cells showed decreased levels of fibrillarin and UBF transcription factor while localization of both proteins in the nucleolus was not impaired. We conclude that withdrawal from cell cycle does not change expression patterns of rDNA variants. However, defects in rRNA processing may lead to fragmentation of nucleoli in senescent cells.

NSUN3-Mediated ROS Accumulation Promotes Hepatocellular Carcinoma Proliferation and Activates PI3K/AKT Pathway

2025-06-23

Haodong Liu , Shijie Liang , Chunting Peng +3 more | Biochemical Genetics

[Retracted] tRNA‑derived fragment tRF‑Glu49 inhibits cell proliferation, migration and invasion in cervical cancer by targeting FGL1

2025-06-23

Yang Wang , Wenying Xia , Fangrong Shen +3 more | Oncology Letters

[This retracts the article DOI: 10.3892/ol.2022.13455.]. [This retracts the article DOI: 10.3892/ol.2022.13455.].

Erianin facilitates pyroptosis in endometrial cancer via targeting m6A reader YTHDF1

2025-06-23

Wan Shu , Xing Zhou , Rong Zhao +7 more | Research Square (Research Square)

<title>Abstract</title> Background Endometrial cancer (EC) is a gynecological malignancy that originates from the endometrial epithelium and has a poor prognosis when advanced, recurrent, or metastatic. The limited therapeutic efficacy and … <title>Abstract</title> Background Endometrial cancer (EC) is a gynecological malignancy that originates from the endometrial epithelium and has a poor prognosis when advanced, recurrent, or metastatic. The limited therapeutic efficacy and severe adverse effects of conventional chemotherapy in advanced EC highlight the urgent need to develop more effective therapeutic drugs. Accumulating clinical evidence has revealed that natural compounds possess pharmacological advantages, including low toxicity and multi-target mechanisms. Erianin is a natural small-molecule compound isolated from <italic>Dendrobium chrysotoxum Lindl</italic> that has multiple pharmacological effects. However, the effects of erianin on EC have not been confirmed and its anticancer mechanisms remain unclear. Methods Erianin was identified as a potent natural compound against EC through compound library screening. The CCK-8 assays, colony formation assays, Edu experiments, and Live/Dead cell staining assays were utilized to analyze the anti-proliferative activity of erianin. Morphological characteristics, transmission electron microscopy, LDH release assays, and Western blot assays were used to evaluate the activation of pyroptosis. A transcriptome sequencing analysis was performed to identify potential mechanism of erianin. We also synthesized biotin-erianin and used a 20k human proteome microarray to identify its direct targets. Molecular docking and CETSA were used to investigate whether erianin binds to YTHDF1. To evaluate the in vivo therapeutic potential of erianin, we established an EC xenograft model and performed mechanistic investigations incorporating H&E staining, IHC staining, and Western blot assays. Results Our results demonstrated that erianin inhibited the cell proliferation of EC cells and promoted pyroptosis through the caspase-3/GSDME pathway. Mechanistically, we established a crucial role for FOXM1/ RRM2-mediated DNA damage in erianin-induced pyroptosis. Protein microarray revealed that erianin-biotin directly targeted m6A reader YTHDF1. We further confirmed that erianin bound to YTHDF1 by molecular docking and CETSA. Molecular studies indicated erianin inhibited YTHDF1 recognized m6A-modified FOXM1 and promoted FOXM1 mRNA degradation, which leads to DNA damage and caspase-3-mediated GSDME cleavage. Erianin also significantly inhibited EC tumor growth in EC models. Conclusion Erianin directly targets YTHDF1 to suppress the FOXM1/RRM2 axis and consequently promotes caspase-3/GSDME-dependent pyroptosis in EC cells. Our findings provide a new strategy for further clinical exploration of EC. Graphical abstract