bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–12–21
nine papers selected by
Connor Rogerson, University of Cambridge
  1. Reconstructing epigenomic dynamics through a single-cell multi-epigenome data integration framework.
  2. Pre-marking chromatin with H3K4 methylation is required for accurate zygotic genome activation and development.
  3. DNA methylation shapes transcription factor binding beyond canonical CpG contexts.
  4. Spatial patterning of the epigenome during vertebrate gastrulation.
  5. Histone H2B monoubiquitylation regulates elongation-to-termination transition in RNA polymerase II transcription.
  6. InCURA: integrative gene clustering based on transcription factor binding sites.
  7. An integrated view of the structure and function of the human 4D nucleome.
  8. Evolution of promoter-proximal pausing enabled a new layer of transcription control.
  9. Chromatin buffers torsional stress during transcription.
  1. Nat Commun. 2025 Dec 17. 16(1): 11006
    Reconstructing epigenomic dynamics through a single-cell multi-epigenome data integration framework.
    Takeru Fujii, Kosuke Tomimatsu, Michiko Kato, Miho Ito, Shoko Sato, Hitoshi Kurumizaka, Yuko Sato, Kazumitsu Maehara, Hiroshi Kimura, Akihito Harada, Yasuyuki Ohkawa.
      Transcriptional regulation arises from the dynamic and combinatorial actions of multiple regulatory factors on genomic DNA. Although many epigenomic regulators have been identified, the precise order in which these factors accumulate at individual gene loci to activate transcription remains unclear. Here we show a single-cell data integration framework that infers the binding order of multiple chromatin factors at single-cell resolution. Central to this framework is sci-mtChIL-seq, a scalable single-cell method that simultaneously profiles genome-wide binding of RNA polymerase II (RNAPII) and diverse epigenomic regulators. By defining transcriptional states through RNAPII occupancy and integrating multiple sci-mtChIL-seq datasets, we systematically link the combinatorial patterns of transcription factor binding, histone modifications and chromatin remodeling. This framework reveals the temporal coordination among chromatin factors during transcriptional activation, providing a powerful approach to uncover context-dependent epigenomic dynamics and the principles of gene regulation in complex cellular systems.
    DOI:  https://doi.org/10.1038/s41467-025-67016-9
  2. Nat Commun. 2025 Dec 19.
    Pre-marking chromatin with H3K4 methylation is required for accurate zygotic genome activation and development.
    Meghana S Oak, Marco Stock, Ana Janeva, Matthias Mezes, Antony M Hynes-Allen, Tobias Straub, Ignasi Forné, Andreas Ettinger, Stephan Hamperl, Axel Imhof, Jelle van den Ameele, Antonio Scialdone, Eva Hörmanseder.
      In vertebrate embryos, gene expression is first initiated at zygotic genome activation (ZGA). Maternally expressed transcription factors are essential for this process. However, it is unknown whether active chromatin modifications established in gametes are present in early embryos and contribute to ZGA and embryonic development. Here, we show that in Xenopus laevis, H3K4me3 occurs at common genomic loci in gametes, in transcriptionally quiescent pre-ZGA embryos, and in transcriptionally active ZGA embryos. These loci exhibit high H3K4me3 intensities and breadth, DNA hypomethylation, and elevated CpG content. We show that H3K4 methylation pre-marking is required for successful ZGA and development, including expression of the key ZGA transcription factor Pou5f3.2. We demonstrate that the H3K4 methyltransferase Cxxc1 ensures establishment of H3K4me3 and proper ZGA. These findings reveal a role for H3K4 methylation in defining active chromatin states in Xenopus laevis embryos and highlight its importance for accurate ZGA and embryonic development.
    DOI:  https://doi.org/10.1038/s41467-025-67692-7
  3. Proc Natl Acad Sci U S A. 2025 Dec 23. 122(51): e2520814122
    DNA methylation shapes transcription factor binding beyond canonical CpG contexts.
    Irina Miodownik, Ruben Solozabal, Michael P O'Hagan, Shira Albeck, Yoav Peleg, Martin Takac, Ariel Afek.
      Cytosine methylation is a key epigenetic modification that regulates transcription factor (TF) binding and gene expression. While most current understanding of methylation-sensitive TF binding derives from studies focused exclusively on fully methylated CpG sites, alternative forms-such as non-CpG and hemimethylation-are increasingly recognized as widespread and functionally important, particularly in embryonic stem cells and neurons. However, the direct impact of these alternative methylation contexts on TF-DNA interactions remains poorly defined, largely because current binding assays introduce methylation enzymatically, which precludes strand-specific and position-resolved measurements. Here, we systematically profile the methylation sensitivity of 18 human TFs spanning 11 structural families using chemically synthesized DNA libraries containing position-specific 5-methylcytosines (5mC) in CpG, non-CpG, and hemimethylated contexts, measured via high-throughput protein-binding microarrays. Our results reveal extensive TF sensitivity to methylation state, position, and strand orientation, including strong binding of several TFs to non-CpG and hemimethylated sites. The presence of 5mC can dramatically alter TF-DNA interactions: transforming low-affinity sites into high-affinity ones by enabling new contacts or silencing otherwise favorable motifs through steric hindrance. Genomic analyses further show that the methylation-sensitive sequences identified in vitro are represented within enhancers and regulatory elements, exhibiting distinct methylation patterns across cell types. Together, our findings uncover a previously hidden layer of methylation-dependent TF-DNA recognition, broadening the understanding of epigenetics in transcriptional regulation.
    Keywords:  epigenetic regulation; forkhead proteins; hemimethylation; non-CpG methylation; transcription factor binding specificity
    DOI:  https://doi.org/10.1073/pnas.2520814122
  4. Nat Commun. 2025 Dec 15.
    Spatial patterning of the epigenome during vertebrate gastrulation.
    Ana Paula Azambuja, Megan Rothstein, Tatiane Y Kanno, Marcos Simoes-Costa.
      A central question in developmental biology is how embryonic cells acquire and store positional information during pattern formation. In vertebrates, this process begins with the localized activation of signaling systems that mediate axial specification. How these spatial cues are recorded within the regulatory landscape of cells has remained unclear. Here, we report that the chromatin landscape of embryonic cells is spatially patterned during gastrulation. Using spatially resolved genomic analysis in avian embryos, we observed that the epigenome becomes organized in gradients of accessibility and activity along the embryonic axes. These chromatin gradients are established within the loci of developmental genes at the onset of gastrulation and can be used to infer the position of cells in the embryo. Our results show that axial specification involves the spatial organization of the epigenome, linking patterns of chromatin activity to the emergence of the embryonic body plan.
    DOI:  https://doi.org/10.1038/s41467-025-67491-0
  5. Commun Biol. 2025 Dec 18. 8(1): 1781
    Histone H2B monoubiquitylation regulates elongation-to-termination transition in RNA polymerase II transcription.
    Tirthankar Bandyopadhyay, Baidehi Basu, Pabitra K Parua.
      RNA Polymerase II (Pol II) transcription is tightly regulated across initiation, elongation, and termination, with key transitions at initiation-to-elongation and elongation-to-termination. While elongation and termination are well-studied, their transition remains unclear. Using chromatin immunoprecipitation (ChIP) and sequencing, we show in Schizosaccharomyces pombe that Cdk9, with its cyclin partner Pch1, disengages from the elongation complex as Pol II nears the cleavage and polyadenylation signal (CPS), while Dis2 (PP1 ortholog) binding increases beyond the CPS, showing an inverse relationship with Cdk9. ChIP-seq analysis reveals histone H2B monoubiquitylation (H2Bub1) regulates Cdk9 occupancy, promoting its recruitment during elongation and dissociation at the CPS, mirroring pSpt5 distribution. Dis2, a pSpt5 phosphatase, exhibits an inverse pattern, decreasing with H2Bub1 loss (htb1-K119R) and increasing with persistent H2Bub1 (ubp8Δ). H2Bub1 perturbations inversely affect Pol II CTD Tyr1/Ser2 phosphorylation, Ser2 kinase Lsk1, mRNA 3'-end processing factors (Pfs2, Pla1), and termination factors (Rhn1, Pcf11)-H2Bub1 loss reduces recruitment, while its persistence enhances occupancy. These findings align with a model in which H2Bub1 loss disrupts termination, whereas its sustained presence reinforces it. Collectively, our findings suggest that H2Bub1-mediated Cdk9 eviction at the CPS facilitates Dis2 binding, pSpt5 dephosphorylation, Pol II slowing, and efficient termination, revealing a yet unknown regulatory paradigm in transcription.
    DOI:  https://doi.org/10.1038/s42003-025-09196-0
  6. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1377. [Epub ahead of print]53(22):
    InCURA: integrative gene clustering based on transcription factor binding sites.
    Lorna Rinck, Ricardo O Ramirez Flores, Julio Saez-Rodriguez, Mahak Singhal.
      Biologically meaningful interpretation of transcriptomic datasets remains challenging, particularly when context-specific gene sets are either unavailable or too generic to capture the underlying biology. We here present InCURA, an integrative clustering strategy based on transcription factor (TF) motif occurrence patterns in gene promoters. InCURA takes as input lists of (i) all expressed genes, used solely to identify dataset-specific expressed TFs, and (ii) differentially regulated genes (DRGs) used for clustering. Promoter sequences of DRGs are scanned for TF binding motifs, and the resulting counts are compiled into a gene-by-TFBS matrix. InCURA then uses unsupervised clustering to infer gene modules with shared predicted regulatory input. Applying InCURA to diverse biological datasets, we uncovered functionally coherent gene modules revealing upstream regulators and regulatory programs that standard enrichment or co-expression analyses fail to detect. In summary, InCURA provides a user-friendly, regulation-centric tool for dissecting transcriptional responses, particularly in settings lacking context-specific gene sets.
    DOI:  https://doi.org/10.1093/nar/gkaf1377
  7. Nature. 2025 Dec 17.
    An integrated view of the structure and function of the human 4D nucleome.
    Job Dekker, Betul Akgol Oksuz, Yang Zhang, Ye Wang, Miriam K Minsk, Shuzhen Kuang, Liyan Yang, Johan H Gibcus, Nils Krietenstein, Oliver J Rando, Jie Xu, Derek H Janssens, Steven Henikoff, Alexander Kukalev, Willemin Andréa, Warren Winick-Ng, Rieke Kempfer, Ana Pombo, Miao Yu, Pradeep Kumar, Liguo Zhang, Andrew S Belmont, Takayo Sasaki, Tom van Schaik, Laura Brueckner, Daan Peric-Hupkes, Bas van Steensel, Ping Wang, Haoxi Chai, Minji Kim, Yijun Ruan, Ran Zhang, Sofia A Quinodoz, Prashant Bhat, Mitchell Guttman, Wenxin Zhao, Shu Chien, Yuan Liu, Sergey V Venev, Dariusz Plewczynski, Ibai Irastorza Azcarate, Dominik Szabó, Christoph J Thieme, Teresa Szczepińska, Mateusz Chiliński, Kaustav Sengupta, Mattia Conte, Andrea Esposito, Alex Abraham, Ruochi Zhang, Yuchuan Wang, Xingzhao Wen, Qiuyang Wu, Yang Yang, Jie Liu, Lorenzo Boninsegna, Asli Yildirim, Yuxiang Zhan, Andrea Maria Chiariello, Simona Bianco, Lindsay Lee, Ming Hu, Yun Li, R Jordan Barnett, Ashley L Cook, Daniel J Emerson, Claire Marchal, Peiyao Zhao, Peter J Park, Burak H Alver, Andrew J Schroeder, Rahi Navelkar, Clara Bakker, William Ronchetti, Shannon Ehmsen, Alexander D Veit, Nils Gehlenborg, Ting Wang, Daofeng Li, Xiaotao Wang, Mario Nicodemi, Bing Ren, Sheng Zhong, Jennifer E Phillips-Cremins, David M Gilbert, Katherine S Pollard, Frank Alber, Jian Ma, William S Noble, Feng Yue.
      The dynamic three-dimensional (3D) organization of the human genome (the 4D nucleome) is linked to genome function. Here we describe efforts by the 4D Nucleome Project1 to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.
    DOI:  https://doi.org/10.1038/s41586-025-09890-3
  8. Nat Struct Mol Biol. 2025 Dec 15.
    Evolution of promoter-proximal pausing enabled a new layer of transcription control.
    Alexandra G Chivu, Brent A Basso, Abderhman Abuhashem, Michelle M Leger, Gilad Barshad, Edward J Rice, Albert C Vill, Wilfred Wong, Shao-Pei Chou, Gopal Chovatiya, Rebecca Brady, Jeramiah J Smith, Athula H Wikramanayake, César Arenas-Mena, Ilana L Brito, Iñaki Ruiz-Trillo, Anna-Katerina Hadjantonakis, John T Lis, James J Lewis, Charles G Danko.
      Promoter-proximal pausing of RNA polymerase (Pol) II is a key regulatory step during transcription. Despite the central role of pausing in gene regulation, we do not understand the evolutionary processes that led to the emergence of Pol II pausing or its transition to a rate-limiting step actively controlled by transcription factors. Here, we analyzed transcription in species across the tree of life. Unicellular eukaryotes display an accumulation of Pol II near transcription start sites, which we propose transitioned to the longer-lived, focused pause observed in metazoans. This transition coincided with the evolution of new subunits in the negative elongation factor (NELF) and 7SK complexes. Depletion of NELF in mammals shifted the promoter-proximal buildup of Pol II from the pause site into the early gene body and compromised transcriptional activation for a set of heat-shock genes. Our work details the evolutionary history of Pol II pausing and sheds light on how new transcriptional regulatory mechanisms evolve.
    DOI:  https://doi.org/10.1038/s41594-025-01718-y
  9. Science. 2025 Dec 18. eadv0134
    Chromatin buffers torsional stress during transcription.
    Jin Qian, Lucyna Lubkowska, Shuming Zhang, Chuang Tan, Yifeng Hong, Xiaomeng Jia, Robert M Fulbright, James T Inman, Taryn M Kay, Joshua Jeong, Glenn Hauk, Deanna Gotte, James M Berger, Mikhail Kashlev, Michelle D Wang.
      During eukaryotic transcription, Pol II must overcome nucleosome obstacles and, because of DNA's helical structure, must also rotate relative to DNA, generating torsional stress. However, there is limited understanding of how Pol II transcribes through nucleosomes while supercoiling DNA. Here, we determined that Pol II generates a torque of 9 pN·nm alone and 13 pN·nm with TFIIS, making it a powerful rotary motor. When Pol II encounters a nucleosome, passage becomes more efficient on a chromatin substrate than on a single-nucleosome substrate, demonstrating that chromatin significantly buffers torsional stress during transcription. Furthermore, topoisomerase supercoiling relaxation allows Pol II to transcribe through multiple nucleosomes. Our results reveal a role of chromatin beyond the more conventional view of it being just a roadblock to transcription.
    DOI:  https://doi.org/10.1126/science.adv0134
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