bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–08–31
fourteen papers selected by
Connor Rogerson, University of Cambridge
  1. IWS1 positions downstream DNA to globally stimulate Pol II elongation.
  2. A fungal chromatin remodeler drives transcription by establishing an open chromatin architecture and activated histone environment.
  3. Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms.
  4. Dual mitotic bookmarking by GAF and H3K27ac orchestrates differential propagation of cell fate memory in neural development.
  5. Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.
  6. Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.
  7. The PRC2-associated factor EPOP is required for Hox gene regulation during axial development in mice.
  8. DNA bendability regulates transcription factor binding to nucleosomes.
  9. Cohesin Loading Factor NIPBL Is Essential for MYCN Expression and MYCN-Driven Oncogenic Transcription in Neuroblastoma.
  10. ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L.
  11. CRISPR with Transcriptional Readout reveals influenza transcription is modulated by NELF and can precipitate an interferon response.
  12. Deciphering chromatin domain, domain community and chromunity for 3D genome maps with Mactop.
  13. TRAFICA: An Open Chromatin Language Model to Improve Transcription Factor Binding Affinity Prediction.
  14. Systema: a framework for evaluating genetic perturbation response prediction beyond systematic variation.
  1. Nat Commun. 2025 Aug 20. 16(1): 7747
    IWS1 positions downstream DNA to globally stimulate Pol II elongation.
    Aiturgan Zheenbekova, James L Walshe, Moritz Ochmann, Moritz Bäuerle, Ute Neef, Kerstin C Maier, Petra Rus, Yumeng Yan, Henning Urlaub, Patrick Cramer, Kristina Žumer.
      The protein IWS1 (Interacts with SPT6 1) is implicated in transcription-associated processes, but a direct role in RNA polymerase (Pol) II function is unknown. Here, we use multi-omics kinetic analysis after rapid depletion of IWS1 in human cells to show that loss of IWS1 results in a global decrease of RNA synthesis and a global reduction in Pol II elongation velocity. We then resolve the cryo-EM structure of the activated Pol II elongation complex with bound IWS1 and elongation factor ELOF1 and show that IWS1 acts as a scaffold and positions downstream DNA within the cleft of Pol II. In vitro assays show that the disordered C-terminal region of IWS1 that contacts the cleft of Pol II is responsible for stimulation of Pol II activity and is aided by ELOF1. Finally, we find that the defect in transcription upon IWS1 depletion leads to a decrease of histone H3 tri-methylation at residue lysine-36 (H3K36me3), but that this secondary effect is an indirect function of IWS1. In summary, our structure-function analysis establishes IWS1 as a Pol II-associated elongation factor that acts globally to stimulate Pol II elongation velocity and ensure proper co-transcriptional histone methylation.
    DOI:  https://doi.org/10.1038/s41467-025-62913-5
  2. Cell Rep. 2025 Aug 20. pii: S2211-1247(25)00940-4. [Epub ahead of print]44(9): 116169
    A fungal chromatin remodeler drives transcription by establishing an open chromatin architecture and activated histone environment.
    Mengting Xu, Qi Zhang, Yuan Li, Wei Zhou, Lingyun Lei, Fucheng Lin, Yanjun Kou, Zeng Tao.
      Chromatin remodelers are central regulators of chromatin architecture and transcriptional dynamics, yet the mechanisms underlying the establishment of transcriptionally permissive chromatin and an activated histone environment remain elusive. In the filamentous fungus Magnaporthe oryzae, we demonstrate that remodeling the structure of chromatin 1 (RSC1) functions as a critical regulator in this process. RSC1 is indispensable for establishing open chromatin architecture, and its activity is tightly correlated with altered nucleosome occupancy. Mechanistically, RSC1 physically associates with a H3K27me3 demethylase and positively modulates its abundance, thereby establishing precise chromatin boundaries to restrict heterochromatin spreading. Additionally, RSC1 recognizes histone acetylation and recruits histone acetyltransferase, which synergistically drive histone hyperacetylation at its targets. By integrating a chromatin remodeling complex, H3K27 demethylation, and histone hyperacetylation, RSC1 orchestrates an activated histone environment to promote transcriptional permissiveness. Collectively, these findings elucidate pivotal roles of RSC1 in counteracting facultative heterochromatin formation, enhancing chromatin accessibility, and activating gene expression in fungi.
    Keywords:  CP: Molecular biology; Chromatin remodelers; H3K27 demethylation; Magnaporthe oryzae; RSC1; chromatin accessibility; histone acetylation; transcriptional activation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116169
  3. Nucleic Acids Res. 2025 Aug 11. pii: gkaf677. [Epub ahead of print]53(15):
    Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms.
    Anna Oncins, Roser Zaurin, Houyem Toukabri, Kimberly Quililan, José R Hernández Mora, Magdalena A Karpinska, Erik Wernersson, Alastair Smith, Agostina Bianchi, Leone Albinati, Luca Cozzuto, Andrea Rivero, Chloe Gulliver, Jessica Velten, Johanna Denkena, François Serra, Raúl Gómez, Cristina López, Sílvia Beà, Jonas Paulsen, Nadia Halidi, Alfonso Valencia, Magda Bienko, A Marieke Oudelaar, Renée Beekman.
      Chromosomal translocations have largely been implicated in tumor development. However, beyond the consequences of aberrant gene expression near the breakpoint, their effects remain underexplored. In this work, we characterize the interplay between translocations, chromatin organization and gene expression using mantle cell lymphoma (MCL) as a model. We show by in vitro genomic engineering and in MCL patient samples that translocations can drive transcriptional changes at entire chromosome arms affecting multiple genes in a regulon-like fashion. Moreover, we demonstrate a clear link between the translocation-induced transcriptional alterations and genome organization, with genes most susceptible to change expression forming pre-existing ultra-long-range interactions spanning 50 megabases. The translocation involves the strong immunoglobulin enhancer into this 3D interaction, allowing the spread of its regulatory potential over the entire affected chromosome arm. Finally, we show that translocation-induced effects mainly represent expression enhancement of genes already active prior to translocation formation, highlighting the importance of the epigenetic state of the cell in which this initial hit occurs. In summary, by studying genome organization principles in the context of translocations, we describe a new principle of gene regulation, showing that strong enhancers can induce substantial gene expression enhancement through ultra-long-range interactions affecting entire chromosome arms, representing an important new mechanism in health and disease.
    DOI:  https://doi.org/10.1093/nar/gkaf677
  4. Nat Commun. 2025 Aug 25. 16(1): 7930
    Dual mitotic bookmarking by GAF and H3K27ac orchestrates differential propagation of cell fate memory in neural development.
    Rulan Zhang, Jie Liu, Zimo Zhang, Zili Chen, Tanpeng Wang, Yuying Shen, Zejun Lan, Jingyi Chu, Haoxuan Tang, Xiyue Zhang, Yan Song.
      In brain development, neural stem cells (NSCs) undergo asymmetric cell divisions to replicate themselves and meanwhile produce differentiating siblings. It remains obscure how NSCs preserve their self-renewing fate across mitosis. Even less is known how cell fate memory is differentially propagated to sibling daughter cells adopting distinct cell fates. Here we found that key differentiation genes are dually bookmarked by pioneer factor GAF (GAGA factor) and H3K27ac in asymmetrically-dividing Drosophila central brain NSCs. In daughter cells adopting NSC fate, GAF promotes self-renewal through timely inhibiting differentiation genes via HDAC1-mediated H3K27 deacetylation, whereas in sibling daughter cells adopting neural progenitor fate, GAF occupancy is replaced by competitor SWI/SNF complex, allowing retention of H3K27ac mark and fast activation of differentiation genes. Thus, our study unveils a paradigm by which cell fate memory can be differentially transmitted to sibling daughter cells via dual antagonistic mitotic bookmarking and selective molecular competition mechanism.
    DOI:  https://doi.org/10.1038/s41467-025-62974-6
  5. Nat Genet. 2025 Aug 20.
    Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.
    Zeyuan Johnson Chen, Sankha Subhra Das, Asha Kar, Seung Hyuk T Lee, Kevin D Abuhanna, Marcus Alvarez, Mihir G Sukhatme, Zitian Wang, Kyla Z Gelev, Matthew G Heffel, Yi Zhang, Oren Avram, Elior Rahmani, Sriram Sankararaman, Markku Laakso, Sini Heinonen, Hilkka Peltoniemi, Eran Halperin, Kirsi H Pietiläinen, Chongyuan Luo, Päivi Pajukanta.
      The cell-type-level epigenomic landscape of human subcutaneous adipose tissue (SAT) is not well characterized. Here, we elucidate the epigenomic landscape across SAT cell types using snm3C-seq. We find that SAT CG methylation (mCG) displays pronounced hypermethylation in myeloid cells and hypomethylation in adipocytes and adipose stem and progenitor cells, driving nearly half of the 705,063 differentially methylated regions (DMRs). Moreover, TET1 and DNMT3A are identified as plausible regulators of the cell-type-level mCG profiles. Both global mCG profiles and chromosomal compartmentalization reflect SAT cell-type lineage. Notably, adipocytes display more short-range chromosomal interactions, forming complex local 3D genomic structures that regulate transcriptional functions, including adipogenesis. Furthermore, adipocyte DMRs and A compartments are enriched for abdominal obesity genome-wide association study (GWAS) variants and polygenic risk, while myeloid A compartments are enriched for inflammation. Together, we characterize the SAT single-cell-level epigenomic landscape and link GWAS variants and partitioned polygenic risk of abdominal obesity and inflammation to the SAT epigenome.
    DOI:  https://doi.org/10.1038/s41588-025-02300-4
  6. Dev Cell. 2025 Aug 13. pii: S1534-5807(25)00496-4. [Epub ahead of print]
    Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.
    Ly-Sha Ee, Daniel Medina-Cano, Emily Goetzler, Christopher Uyehara, Clayton Schwarz, Eralda Salataj, Subhashini Madhuranath, Todd Evans, Anna-Katerina Hadjantonakis, Effie Apostolou, Alexander Polyzos, Thomas Vierbuchen, Matthias Stadtfeld.
      The molecular mechanisms that drive essential patterning events in the mammalian embryo remain poorly understood. Analysis of transcription factor expression kinetics at peri-gastrulation stages of development suggest Otx2 as a candidate regulator of the definitive endoderm, the precursor of all gut-derived organs. Accordingly, timed OTX2 depletion in gastruloids or during directed differentiation results in abnormal definitive endoderm specification in mouse and human, characterized by altered expression of components and transcriptional targets of the canonical WNT signaling pathway, perturbed adhesion and migration programs, and de-repression of regulators of other lineages. These defects cumulate in impaired foregut formation. Mechanistically, OTX2 is required to activate a subset of endoderm-specific enhancers and to suppress select enhancers of other lineages, allowing timely exit from the primitive streak and correct specification of anterior endoderm. Our results establish OTX2 as an early gut regulator and suggest molecular principles underlying spatiotemporal cell identity conserved across germ layers and species.
    Keywords:  H3K27ac; OTX2; anterior-posterior; definitive endoderm; enhancers; foregut; gastrulation; germ layer specification; patterning; transcription factor
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.020
  7. Dev Biol. 2025 Aug 18. pii: S0012-1606(25)00231-3. [Epub ahead of print]527 250-259
    The PRC2-associated factor EPOP is required for Hox gene regulation during axial development in mice.
    Ivano Mocavini, Anna Mallol, Arantxa Gutierrez, Paul Chammas, Ana Carretero, André Dias, Enrique Blanco, Irene Rodriguez Arce, Moises Mallo, Luciano Di Croce, Bernhard Payer.
      The Polycomb repressive complex 2 (PRC2) is an essential modulator of gene repression. We previously reported that, in mouse embryonic stem cells, PRC2 associates with elonginB/C through EPOP, which allows for low-level expression of target genes. Here we investigate the role of EPOP in vivo by generating a mouse knockout (KO) model. We show that Epop KO mice are viable and fertile but display highly penetrant posterior homeotic transformations of the axial skeleton, which can be partially recapitulated by deletion of only the maternal allele. Epop-depleted embryos present a shift of the anterior boundary of expression of certain Hox genes. Tissue-specific RNA sequencing of embryos suggests that the Hox activation defect originates at the level of the presomitic mesoderm. Overall, we find that EPOP prevents premature activation of a subset of Hox genes, and that this is required for correct body patterning along the antero-posterior axis.
    Keywords:  Body patterning; EPOP; Hox genes; PRC2; Polycomb
    DOI:  https://doi.org/10.1016/j.ydbio.2025.08.014
  8. Nat Struct Mol Biol. 2025 Aug 25.
    DNA bendability regulates transcription factor binding to nucleosomes.
    Luca Mariani, Xiao Liu, Kwangwoon Lee, Stephen S Gisselbrecht, Philip A Cole, Martha L Bulyk.
      Cell fates are controlled by 'pioneers', sequence-specific transcription factors (TFs) that bind recognition motifs on nucleosomes ('pioneer binding'). Pioneers occupy a minority of their recognition sequences in the genome, suggesting that the sequence context regulates their binding. Here we developed PIONEAR-seq, a high-throughput biochemical assay to characterize pioneer binding. We used PIONEAR-seq to assay 11 human TFs for binding to nucleosomes based on Widom 601 versus genomic sequences. We found that pioneer binding, while mediated primarily by the recognition motifs of TFs, is regulated by the broader nucleosome sequence context. Certain TFs, found to be dyad or periodic binders on nucleosomes assembled on synthetic sequences, exhibited end binding to nucleosomes based on genomic sequences. We propose a model where the local bendability of the DNA sequence in nucleosomes is involved in positioning pioneer binding, and thus represents another cis-regulatory layer in eukaryotic genomes.
    DOI:  https://doi.org/10.1038/s41594-025-01633-2
  9. Cancers (Basel). 2025 Aug 09. pii: 2615. [Epub ahead of print]17(16):
    Cohesin Loading Factor NIPBL Is Essential for MYCN Expression and MYCN-Driven Oncogenic Transcription in Neuroblastoma.
    Jee-Youn Kang, Kaitlyn A Tremble, Philip Homan, Carol J Thiele.
      High-risk neuroblastoma remains a major clinical challenge, with a five-year survival rate below 50% despite intensive multimodal therapies. MYCN amplification, a hallmark of high-risk disease, drives an aggressive transcriptional program that maintains undifferentiated and proliferative states in neuroblastoma cells. Given its central role in oncogenic transcription, MYCN represents an attractive therapeutic target; however, its undruggable nature has prompted efforts to identify upstream regulators or cofactors that sustain MYCN expression and oncogenic function. In this study, we investigate the role of the cohesin loading factor NIPBL in supporting the MYCN-driven transcriptional program. We demonstrate that elevated NIPBL expression is associated with undifferentiated, proliferative neuroblastoma cell states and poor clinical outcomes in neuroblastoma patients. Functionally, NIPBL depletion reduces MYCN mRNA and protein levels and induces widespread transcriptional reprogramming consistent with neuronal differentiation. These transcriptional changes are accompanied by decreased neuroblastoma cell proliferation and increased neuronal differentiation, reflecting impaired regulation of MYCN target genes upon NIPBL loss. Collectively, we have established a mechanistic link between NIPBL and the MYCN-driven transcriptome, highlighting NIPBL as a potential therapeutic vulnerability to promote differentiation in high-risk neuroblastoma.
    Keywords:  MYCN; NIPBL; cohesion; neuroblastoma; transcription
    DOI:  https://doi.org/10.3390/cancers17162615
  10. Nat Genet. 2025 Aug 26.
    ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L.
    Weiran Feng, Erik Ladewig, Matthew Lange, Nazifa Salsabeel, Huiyong Zhao, Young Sun Lee, Anuradha Gopalan, Hanzhi Luo, Wenfei Kang, Ning Fan, Eric Rosiek, Elisa de Stanchina, Yu Chen, Brett S Carver, Christina S Leslie, Charles L Sawyers.
      Despite the high prevalence of ERG transcription factor translocations in prostate cancer, the mechanism of tumorigenicity remains poorly understood. Using lineage tracing, we find the tumor-initiating activity of ERG resides in a subpopulation of murine basal cells that coexpress luminal genes (BasalLum) and not in the larger population of ERG+ luminal cells. Upon ERG activation, BasalLum cells give rise to highly proliferative intermediate (IM) cells with stem-like features that coexpress basal, luminal, hillock and club marker genes, before transitioning to Krt8+ luminal cells. Transcriptomic analysis of ERG+ human prostate cancers confirms the presence of rare ERG+ BasalLum cells, as well as IM cells whose presence is associated with a worse prognosis. Single-cell analysis revealed a chromatin state in ERG+ IM cells enriched for STAT3 transcription factor binding sites and elevated expression of the KMT2A/MLL1 and DOT1L, all three of which are essential for ERG-driven tumorigenicity in vivo. In addition to providing translational opportunities, this work illustrates how single-cell approaches combined with lineage tracing can identify cancer vulnerabilities not evident from bulk analysis.
    DOI:  https://doi.org/10.1038/s41588-025-02289-w
  11. Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2515564122
    CRISPR with Transcriptional Readout reveals influenza transcription is modulated by NELF and can precipitate an interferon response.
    Alison C Vicary, Sydney N Z Jordan, Marisa Mendes, Sharmada Swaminath, Lennice K Castro, Justin S Porter, Kevin D Vo, Alistair B Russell.
      Transcription of interferons upon viral infection is critical for cell-intrinsic innate immunity. This process is influenced by many host and viral factors. To identify host factors that modulate interferon induction within cells infected by influenza A virus, we developed CRISPR with Transcriptional Readout using sequencing (CRITR-seq). CRITR-seq is a method linking CRISPR guide sequence to activity at a promoter of interest. Employing this method, we find that depletion of the Negative Elongation Factor (NELF) complex increases both flu transcription and interferon expression. We find that the process of flu transcription, both in the presence and absence of viral replication, is a key contributor to interferon induction. Taken together, our findings highlight innate immune ligand concentration as a limiting factor in triggering an interferon response, identify NELF as an important interface with the flu life cycle, and validate CRITR-seq as a tool for genome-wide screens for phenotypes of gene expression.
    Keywords:  CRISPR screen; influenza virus; innate immunity; interferon; transcription
    DOI:  https://doi.org/10.1073/pnas.2515564122
  12. Commun Biol. 2025 Aug 27. 8(1): 1290
    Deciphering chromatin domain, domain community and chromunity for 3D genome maps with Mactop.
    Ran Duan, Dachang Dang, Shichen Fan, Shaowen Yao, Shihua Zhang.
      Advanced high-throughput chromosome conformation capture techniques, like Hi-C, reveal genome organization into structural units like topologically associating domains (TADs), which are crucial in gene expression regulation. While accurately identifying TADs is vital, distinguishing different types of TAD boundaries and TAD categories remains a significant challenge in genomic research. We develop a Markov clustering-based tool, Mactop, to accurately identify TADs and provide biologically important classifications of TADs and their boundaries. Mactop distinguishes stable and dynamic boundaries based on biological significance. Mactop shows superior performance against multiple TAD-calling methods. More importantly, leveraging spatial interactions among TADs, Mactop uncovers TAD communities characterized by chromatin accessibility and enriched histone modifications. Mactop unveils the 'chromunity' within TADs in high-order interaction data, showing that interactions within TADs are diverse rather than uniform. In short, Mactop is a versatile, accurate, robust tool for deciphering chromatin domain, domain community, and chromunity for 3D genome maps.
    DOI:  https://doi.org/10.1038/s42003-025-07635-6
  13. Bioinformatics. 2025 Aug 23. pii: btaf469. [Epub ahead of print]
    TRAFICA: An Open Chromatin Language Model to Improve Transcription Factor Binding Affinity Prediction.
    Yu Xu, Chonghao Wang, Ke Xu, Yi Ding, Aiping Lyu, Lu Zhang.
       MOTIVATION: In silico transcription factor and DNA (TF-DNA) binding affinity prediction plays a vital role in examining TF binding preferences and understanding gene regulation. The existing tools employ TF-DNA binding profiles from in vitro high-throughput technologies to predict TF-DNA binding affinity. However, TFs tend to bind to sequences in open chromatin regions in vivo, such TF binding preference is seldomly considered by these existing tools.
    RESULTS: In this study, we developed TRAFICA, an open chromatin language model to predict TF-DNA binding affinity by integrating sequence characteristics of open chromatin regions from ATAC-seq experiments and in vitro TF-DNA binding profiles from high-throughput technologies. We pre-trained TRAFICA on over 2.8 million nucleotide sequences in open chromatin regions derived from 197 ATAC-seq experiments (115 cell lines) to learn in vivo TF binding preferences. We further fine-tuned TRAFICA using low-rank adaptation (LoRA) on PBM and HT-SELEX TF-DNA binding profiles to learn intrinsic binding preferences for specific TFs. We systematically evaluated TRAFICA and compared its predictive performance with existing prediction tools and advanced DNA language models. The experimental results demonstrated that TRAFICA significantly outperformed the others in predicting in vitro and in vivo TF-DNA binding affinity, achieving state-of-the-art performance. These findings indicate that considering the sequence characteristics from open chromatin regions could significantly improve TF-DNA binding affinity prediction.
    AVAILABILITY AND IMPLEMENTATION: The source code of TRAFICA and detailed tutorials are available at https://github.com/ericcombiolab/TRAFICA.
    SUPPLEMENTARY INFORMATION: Supplementary files are available at Bioinformatics Journal online.
    Keywords:  DNA Language Models; Open Chromatin Regions; Transcription Factor Binding Affinity
    DOI:  https://doi.org/10.1093/bioinformatics/btaf469
  14. Nat Biotechnol. 2025 Aug 25.
    Systema: a framework for evaluating genetic perturbation response prediction beyond systematic variation.
    Ramon Viñas Torné, Maciej Wiatrak, Zoe Piran, Shuyang Fan, Liangze Jiang, Sarah A Teichmann, Mor Nitzan, Maria Brbić.
      Predicting transcriptional responses to genetic perturbations is challenging in functional genomics. While recent methods aim to infer effects of untested perturbations, their true predictive power remains unclear. Here, we show that current methods struggle to generalize beyond systematic variation, the consistent transcriptional differences between perturbed and control cells arising from selection biases or confounders. We quantify this variation in ten datasets, spanning three technologies and five cell lines, and show that common metrics are susceptible to these biases, leading to overestimated performance. To address this, we introduce Systema, an evaluation framework that emphasizes perturbation-specific effects and identifies predictions that correctly reconstruct the perturbation landscape. Using this framework, we uncover insights into the predictive capabilities of existing methods and show that predicting responses to unseen perturbations is substantially harder than standard metrics suggest. Our work highlights the importance of heterogeneous gene panels and disentangles predictive performance from systematic effects, enabling biologically meaningful developments in perturbation response modeling.
    DOI:  https://doi.org/10.1038/s41587-025-02777-8
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