bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–11–23
nine papers selected by
Connor Rogerson, University of Cambridge
  1. Omnireg-gpt: a high-efficiency foundation model for comprehensive genomic sequence understanding.
  2. The specificity landscape of WRKY transcription factors reveals the bidirectional influence of non-CG methylation.
  3. ATACdb 2.0: a comprehensive chromatin accessibility database of human and mouse.
  4. Genetic elements promote retention of extrachromosomal DNA in cancer cells.
  5. KLF5 enables dichotomous lineage programs in pancreatic cancer via the AAA+ ATPase coactivators RUVBL1 and RUVBL2.
  6. Single-cell activation screen identifies hepatic maturation regulators with zonal resolution.
  7. High-throughput capture of actively transcribed region-interacting sequences reveals an intricate promoter-centered regulatory network.
  8. Adenine DNA methylation associated with transcriptionally permissive chromatin is widespread across eukaryotes.
  9. Rewiring cancer epigenome: lncRNA as modulator of chromatin architecture and neoplastic transformation.
  1. Nat Commun. 2025 Nov 19. 16(1): 10139
    Omnireg-gpt: a high-efficiency foundation model for comprehensive genomic sequence understanding.
    Aowen Wang, Jiaqi Li, Hongyu Dong, Bocheng Xu, Qingyu Yin, Yanchao Xu, Jie Fu, Junbo Zhao.
      The human genome contains a sophisticated array of elements that regulate gene activity and organismal functions. Developing a large window foundation model capable of efficiently processing long sequence inputs is essential yet challenging for decoding the multi-layered and complex landscape of the cis-regulatory elements. Here, we introduce OmniReg-GPT, a generative foundation model designed for the low-resource pretraining of long genomic sequences by optimized attention mechanism. During pretraining, OmniReg-GPT captures the complete distribution of regulatory elements across nucleotide to megabase scales with efficient training speed and memory usage. We demonstrate exceptional performance in downstream regulotary applications spanning the entire spectrum of genomic scales, including various cis-regulatory elements identification, context dependent gene expression prediction, single-cell chromatin accessibility analysis, and 3D chromatin contact modeling. As a generative model, OmniReg-GPT also holds the potential to generate candidate cell-type-specific enhancers through prompt engineering. Overall, OmniReg-GPT extends the boundaries of foundation models in the genomic field, and provides a valuable pretraining model resource which can be extensively applied for genomic researches.
    DOI:  https://doi.org/10.1038/s41467-025-65066-7
  2. Nucleic Acids Res. 2025 Nov 13. pii: gkaf1168. [Epub ahead of print]53(21):
    The specificity landscape of WRKY transcription factors reveals the bidirectional influence of non-CG methylation.
    Nana Ma, Dingkun Jiang, Tian Li, Lin Luo, Hao Chen, Xinfeng Zhang, Zongkai Mu, Shuyan Chen, Piaojuan Chen, Qing Liu, Juncheng Lin, Qin Wang, Yimeng Yin, Jussi Taipale, Jing Huang, Honghong Guo, Fangjie Zhu.
      A distinct epigenetic feature of plants is the DNA methylation in non-CG contexts. Although the physiological roles of non-CG methylation have been elucidated, its direct impact on transcription factor (TF)-DNA interactions remains largely unexplored. Focusing on WRKY-family TFs, here we investigated how non-CG methylation influences their DNA binding specificity and genome-wide cis-regulatory elements (CREs). By generating 461 SELEX and DAP-seq libraries for 54 AtWRKYs, we show that DNA methylation alters both monomeric and dimeric binding specificities of WRKYs, leading to an overall increase in specificity divergence among family members. We curated 201 WRKY motifs and clustered them into 11 classes, 5 of which represent previously unreported specificities. Notably, the known WRKY cis-element PRE4 was found to be recognized only when methylated. The comprehensive dataset of accurate WRKY motifs also enabled the identification of the amino acid discriminants of W-box and WT-box. Expanding on prior knowledge, we demonstrate that methylation not only decreases but can also increase the affinity of WRKYs. This bidirectional effect has globally reshaped the genomic binding landscape of WRKYs upon methylation. Finally, we constructed the WRKY Regulatory Code Database (https://transysbio.cn/WRKYRCDB.php) to facilitate data access.
    DOI:  https://doi.org/10.1093/nar/gkaf1168
  3. Nucleic Acids Res. 2025 Nov 17. pii: gkaf1222. [Epub ahead of print]
    ATACdb 2.0: a comprehensive chromatin accessibility database of human and mouse.
    Qiao-Li Fang, Feng-Cui Qian, Zheng-Min Yu, Bing-Long Li, Xiang-Yang Meng, Ting Cui, Ting-Ting Yu, Yan-Yu Li, Li-Dong Li, Chen-Chen Feng, Zi-Rui Xiong, Qing Xun, Chun-Quan Li, Qiu-Yu Wang.
      Chromatin accessibility, which reflects transcriptional activity, is crucial for elucidating gene regulation, cellular function, and disease mechanisms. To provide a more comprehensive chromatin accessibility resource, we have released ATACdb 2.0 (https://www.licpathway.net/ATACdb/), which provides multiple significant improvements over ATACdb 1.0: (i) Substantially expands the data scale by adding new mouse data and expanding human samples, while constructing pseudo-bulk ATAC-seq profiles based on scATAC-seq data to enrich cell type diversity. The current version contains 319 968 559 chromatin accessibility regions (CARs) from 4 031 human samples and 75 639 252 CARs from 1273 mouse samples. Compared with version 1.0, the numbers of samples and regions have increased by 3.5- and 7.5-fold, respectively. (ii) Provides richer genetic and epigenetic regulatory annotations, including silencer regions, CpG islands, meQTLs, histone modifications, eRNAs, transcription co-factors (TcoFs) and transcription factors (TFs), etc. (iii) Adds practical and convenient search and analysis functions, including "Search by SNP", "Genomic regions enrichment analysis", and "Gene-CARs overlapping analysis". (iv) Optimized target gene identification methods and added enrichment analysis of target genes. (v) Provides two additional data quality control metrics. In summary, ATACdb 2.0 provides more comprehensive and reliable resources along with more convenient and flexible functionalities, facilitating the exploration of the role of chromatin accessibility in gene regulation.
    DOI:  https://doi.org/10.1093/nar/gkaf1222
  4. Nature. 2025 Nov 19.
    Genetic elements promote retention of extrachromosomal DNA in cancer cells.
    Venkat Sankar, King L Hung, Aditi Gnanasekar, Ivy Tsz-Lo Wong, Quanming Shi, Katerina Kraft, Matthew G Jones, Britney Jiayu He, Xiaowei Yan, Julia A Belk, Kevin J Liu, Sangya Agarwal, Sean K Wang, Anton G Henssen, Paul S Mischel, Howard Y Chang.
      Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer1,2. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division3-6 and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear3,7. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter-enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome.
    DOI:  https://doi.org/10.1038/s41586-025-09764-8
  5. Nat Commun. 2025 Nov 15. 16(1): 9996
    KLF5 enables dichotomous lineage programs in pancreatic cancer via the AAA+ ATPase coactivators RUVBL1 and RUVBL2.
    Patrick J Cunniff, Nicole Sivetz, Damianos Skopelitis, Olaf Klingbeil, Daniel Toobian, Diogo Maia-Silva, Mikala Egeblad, Christopher R Vakoc.
      Lineage plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor heterogeneity and therapeutic resistance. Here, we identify KLF5 as a dynamic master regulator of epithelial lineage identity in PDAC, with dichotomous roles in promoting either classical or basal-like transcriptional programs. Through unbiased proteomic and genetic screens, we uncover the AAA+ ATPases RUVBL1 and RUVBL2 as essential coactivators of KLF5 across both lineage states. We demonstrate that ATP hydrolysis by RUVBL1/2 is required for the stable interaction with an intrinsically disordered region of KLF5, enabling its recruitment to lineage-specific enhancers and driving transcriptional regulation of identity-defining genes. Notably, small-molecule inhibitors of RUVBL1/2 ATPase activity, which have anti-PDAC activity in vivo, suppress KLF5-dependent transcription. These findings define a previously unrecognized mechanism of ATP hydrolysis-dependent transcriptional coactivation and highlight a potential therapeutic strategy for modulating aberrant lineage programs in cancer.
    DOI:  https://doi.org/10.1038/s41467-025-66007-0
  6. Dev Cell. 2025 Nov 20. pii: S1534-5807(25)00665-3. [Epub ahead of print]
    Single-cell activation screen identifies hepatic maturation regulators with zonal resolution.
    Atsuhiro Taguchi, Alexandre P Magalhães, Adriano Bolondi, Ming-Kang Lee, Helene Kretzmer, Lars Wittler, Denes Hnisz, Alexander Meissner.
      The maturation of lineage-committed embryonic hepatocytes requires both the timed activation of metabolic gene regulatory networks (GRNs) and silencing of embryonic programs to achieve adult hepatic functions. However, in vitro derivation of mature hepatocytes remains imperfect, and key transcriptional regulators governing GRN rewiring during late development are still insufficiently defined. To address this, we generated a developmental reference atlas and employed a dCas9 activation screen with single-cell transcriptomics on primary mouse embryonic hepatocytes, enabling effect ranking among late-onset transcription regulators. We identify Nr1i3 as a potent inducer of pericentrally expressed metabolic genes and Nfix as a critical suppressor of embryonic and periportal signatures. Supplementing liver zonation patterning signals with these regulators further enhanced the expression of pericentrally zonated metabolic genes, emphasizing the importance of a microenvironment-targeted approach. Our screening and analysis therefore highlight regulatory mechanisms underlying organ maturation and offer general strategies for improving the functionality of in vitro-derived cells.
    Keywords:  CRISPR-screening; Cyp; Nfix; Nr1i3; development; liver; liver zonation; maturation; single cell; transcription factor
    DOI:  https://doi.org/10.1016/j.devcel.2025.10.014
  7. Mol Cell. 2025 Nov 18. pii: S1097-2765(25)00859-7. [Epub ahead of print]
    High-throughput capture of actively transcribed region-interacting sequences reveals an intricate promoter-centered regulatory network.
    Xinxin Li, Jinsheng Xu, Xiaohao Yan, Jiayong Zhong, Chunhui Hou, Chuanle Xiao, Longjian Niu, Wei Chi.
      Understanding the intricate relationship between three-dimensional chromatin structure and gene expression regulation is essential for cellular biology. However, current techniques are insufficient to capture regulatory elements functioning through three-dimensional chromatin structures. Here, we present high-throughput capture of actively transcribed region-interacting sequences (Hi-Coatis), a high-throughput method that seamlessly integrates the detection of active transcription signals with three-dimensional chromatin interaction studies. Hi-Coatis operates without antibodies or probes, enabling low-input cell experiments with high resolution and robustness, capturing more than 93% of expressed genes and over 60,000 regulatory loci in human cells. The repetitive/copy number variation (CNV) regions and the promoter regions of C2 genes, defined by the distribution patterns of Hi-Coatis signals, both exhibit strong regulatory element activity. Notably, in the Hemin-induced erythroid differentiation model of K562 cells, Hi-Coatis uncovers the potential for silent genes to transition to transcriptionally active states through the cooperative influence of specific transcription factors (e.g., CCCTC-binding factor [CTCF] and cohesin complex subunits Rad21 [RAD21]) and regulatory elements.
    Keywords:  3D chromatin interactions; Hi-Coatis; actively transcribed regions; gene regulation; regulatory elements; repetitive genomic elements
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.018
  8. Nat Genet. 2025 Nov 18.
    Adenine DNA methylation associated with transcriptionally permissive chromatin is widespread across eukaryotes.
    Pedro Romero Charria, Cristina Navarrete, Vladimir Ovchinnikov, Lan Xu, Luke A Sarre, Victoria Shabardina, Ewa Ksiezopolska, Elena Casacuberta, David Lara-Astiaso, Arnau Sebé-Pedrós, Alex de Mendoza.
      DNA methylation is a key regulator of eukaryotic genomes, most commonly through 5-methylcytosine (5mC). In contrast, the existence and function of N6-methyladenine (6mA) in eukaryotes have been controversial, with conflicting reports resulting from methodological artifacts. Nevertheless, some unicellular lineages, including ciliates, early-branching fungi and the alga Chlamydomonas, show robust 6mA signals, raising questions about their origin and evolutionary role. Here we apply Oxford Nanopore sequencing to profile 6mA at base-pair resolution across 18 unicellular eukaryotes representing all major supergroups. We find that robust 6mA patterns occur only in species that encode the adenine methyltransferase AMT1. Notably, 6mA consistently accumulates downstream of transcriptional start sites, positioned between H3K4me3-marked nucleosomes, indicating a conserved association with transcriptional activation. Our results support the idea that the last eukaryotic common ancestor had a dual methylation system, with transcription-linked 6mA and repressive 5mC, which has been repeatedly simplified in both multicellular and unicellular lineages through the loss of the AMT1 pathway.
    DOI:  https://doi.org/10.1038/s41588-025-02409-6
  9. Mamm Genome. 2025 Nov 19. 37(1): 3
    Rewiring cancer epigenome: lncRNA as modulator of chromatin architecture and neoplastic transformation.
    Santosh Kumar, Subhadip Kundu, Surender K Sharawat, Ashok Sharma.
      Epigenetic rewiring modulates gene expression by reshaping chromatin architecture without altering the underlying DNA sequence. The eukaryotic genome is intricately folded within a dynamic three-dimensional nuclear architecture, which is vital for maintaining genomic integrity and ensuring spatially precise gene regulation. Long non-coding RNAs (lncRNAs), a class of regulatory transcripts, play a pivotal role in organizing nuclear structure, preserving cell identity, and sustaining complex regulatory networks. Through interactions with DNA, RNA, transcription factors, and chromatin-modifying complexes, lncRNAs influence the formation and maintenance of higher-order chromatin structures, including topologically associating domains (TADs), lamina-associated domains (LADs), and chromatin loops. These structural frameworks facilitate or constrain long-range genomic interactions, thereby governing transcriptional programs. Aberrant lncRNA expression disrupts this regulatory architecture and is increasingly recognized as a driving force in oncogenesis. Notable lncRNAs, such as XIST, HOTAIR, and MALAT1, modulate gene expression by recruiting epigenetic regulators, including Polycomb Repressive Complex 2 (PRC2), which alters histone modifications and DNA methylation landscapes, and rewires enhancer-promoter contacts. These mechanisms underlie profound transcriptional reprogramming in cancer cells. Technological advances in genome conformation capture methods (e.g., Hi-C, 3C) have enabled high-resolution mapping of these dynamic chromatin interactions, revealing the extent of lncRNA-mediated 3D genome remodeling in malignancy. This review synthesizes emerging evidence on the role of lncRNAs in shaping nuclear architecture and gene regulation, with a focus on their oncogenic and tumor-suppressive functions. By integrating insights into chromatin topology and epigenetic control, we underscore the potential of targeting lncRNAs and associated chromatin remodeling pathways as innovative diagnostic and therapeutic strategies in cancer and other complex diseases.
    Keywords:  Cancer; Epigenetics; Genome organization; lncRNA
    DOI:  https://doi.org/10.1007/s00335-025-10172-6
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