bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2026–01–25
eleven papers selected by
Connor Rogerson, University of Cambridge
  1. Distal enhancers regulate mammalian early embryonic lineage differentiation through long-range interactions.
  2. Structural analysis of OCT4 binding to human LIN28B nucleosomes.
  3. Chromatin state architecture governs transcription factor accessibility across plant genomes.
  4. ATAD2 mediates chromatin-bound histone chaperone turnover.
  5. Hierarchical mechanisms control the clearance of DNA lesion-stalled RNA polymerase II.
  6. Evaluating single-cell ATAC-seq atlasing technologies using sequence-to-function modeling.
  7. Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease.
  8. Superenhancers shape the landscape and repair dynamics of transcription-associated DNA breaks in cancer.
  9. CLAMP: predicting specific protein-mediated chromatin loops in diverse species with a chromatin accessibility language model.
  10. Critical role for a high-plasticity cell state in lung cancer.
  11. Pooled single-cell screen in colorectal cancer defines transcriptional modules linked to oncogenes.
  1. Nucleic Acids Res. 2026 Jan 14. pii: gkag026. [Epub ahead of print]54(2):
    Distal enhancers regulate mammalian early embryonic lineage differentiation through long-range interactions.
    Qianshu Zhu, Shimeng Guo, Juan Xie, Jiadan Qu, Xiaoyu Wan, Sicong Liang, Xiaoyu Liu, Ling Zhu, Jie Wang, Sheng Yang, Qiang Dong, Guoning Huang, Shaorong Gao, Mo Chen, Jingyu Li.
      Histone modifications are key regulators of cell lineage differentiation; however, the roles of histone H3 lysine 27 acetylation (H3K27ac) and high-order chromatin structure in the trophectoderm (TE) and inner cell mass (ICM) remain unclear. Using ultra-low-input multi-omics, we profiled H3K27ac, chromatin accessibility, and the transcriptome in both the TE and ICM. Lineage-specific H3K27ac was predominantly enriched at distal enhancers rather than promoters, indicating that first-lineage differentiation relies on distal enhancer activity. Integration with chromatin accessibility data identified key transcription factors cooperating with H3K27ac during peri-implantation. Analysis of high-order chromatin structure revealed lineage-specific enhancer-promoter loops. Further, we identified and functionally validated BRD4, p300, and YY1 at these enhancers, demonstrating their essential roles in morula-to-blastocyst transition. Notably, CBP/p300 inhibition selectively disrupted distal H3K27ac-marked enhancers with minimal effects on promoters, leading to down-regulation of placenta-related genes. Despite similar accessibility and transcription factor binding between the TE and ICM, enhancer activity requires H3K27ac acquisition rather than accessibility alone. These results indicate that H3K27ac-marked distal enhancers regulate early lineage differentiation by promoting lineage-specific gene expression through long-range chromatin interactions. Cross-species comparisons between mice and humans further revealed stronger H3K27ac conservation in the TE than in the ICM of mammalian embryos, highlighting the conserved regulatory role of TE-specific enhancers during early development.
    DOI:  https://doi.org/10.1093/nar/gkag026
  2. Sci Rep. 2026 Jan 19.
    Structural analysis of OCT4 binding to human LIN28B nucleosomes.
    Kalyan K Sinha, Mario Halic.
      Structural studies of nucleosomes most commonly involve histones from Xenopus species or humans. Yet, the effect of subtle differences in the amino acid sequences of these histones on key aspects of structure, such as nucleosome assembly, DNA positioning, and transcription factor binding remains unclear. Here, we show that histones from both species can efficiently assemble on the human LIN28B DNA sequence. Using cryogenic electron microscopy we demonstrate that the pioneer transcription factor OCT4 engages with LIN28B nucleosomes assembled with human histones in the same manner as observed in our previous work in which the nucleosomes were assembled with Xenopus histones.
    Keywords:  Chromatin; Cryo-EM; Gene regulation; Nucleosome; Pioneer transcription factor
    DOI:  https://doi.org/10.1038/s41598-026-35959-8
  3. PLoS Genet. 2026 Jan 22. 22(1): e1012015
    Chromatin state architecture governs transcription factor accessibility across plant genomes.
    Vikas Shukla, Elin Axelsson, Tetsuya Hisanaga, Jim Haseloff, Frédéric Berger, Facundo Romani.
      The complexity of varied modifications of chromatin composition is integrated in archetypal combinations called chromatin states that predict the local potential for transcription. The degree of conservation of chromatin states has not been established amongst plants, and how they interact with transcription factors is unknown. Here we identify and characterize chromatin states in the flowering plant Arabidopsis thaliana and the bryophyte Marchantia polymorpha, showing a large degree of functional conservation over more than 450 million years of land plant evolution. We used this new resource of conserved plant chromatin states to understand the influence of chromatin states on gene regulation. We established the preferential association of chromatin states with binding sites and activity of transcription factors. These associations define three main groups of transcription factors that bind upstream of the transcription start site, at the + 1 nucleosome or further downstream of the transcription start site and broadly associate with distinct biological functions including a list of potential candidate pioneer factors we know little about in plants, compared to their important roles in animal stem cells and early development.
    DOI:  https://doi.org/10.1371/journal.pgen.1012015
  4. Elife. 2026 Jan 20. pii: RP107582. [Epub ahead of print]14
    ATAD2 mediates chromatin-bound histone chaperone turnover.
    Ariadni Liakopoulou, Fayçal Boussouar, Daniel Perazza, Sophie Barral, Emeline Lambert, Tao Wang, Florent Chuffart, Ekaterina Bourova-Flin, Charlyne Gard, Denis Puthier, Sophie Rousseaux, Christophe Arnoult, André Verdel, Saadi Khochbin.
      ATAD2, a conserved protein which is predominantly expressed in embryonic stem (ES) cells and spermatogenic cells, emerges as a crucial regulator of chromatin plasticity. Our previous parallel studies conducted in both ES cells and S. pombe highlighted the fundamental role of ATAD2 in facilitating chromatin-bound histone chaperone turnover. Focusing on mouse spermatogenesis, we demonstrate here that ATAD2 regulates the HIRA-dependent localization of H3.3 on the genome and influences H3.3-mediated gene transcription. Moreover, by modulating histone eviction and the assembly of protamines, ATAD2 ensures proper chromatin condensation and genome packaging in mature sperm. Disruption of Atad2 function in mice leads to abnormal genome organization in mature spermatozoa. Together, these findings establish a previously overlooked level of chromatin dynamic regulation, governed by ATAD2-controlled histone chaperones binding to chromatin, which defines the balance between histone deposition and removal.
    Keywords:  Atad2; Spermatogenesis; chaperone turnover; chromatin dynamics; chromosomes; gene expression; mouse
    DOI:  https://doi.org/10.7554/eLife.107582
  5. Nat Commun. 2026 Jan 19.
    Hierarchical mechanisms control the clearance of DNA lesion-stalled RNA polymerase II.
    Paula J van der Meer, George Yakoub, Kotaro Tsukada, Yuka Nakazawa, Tomoo Ogi, Martijn S Luijsterburg.
      Stalling of elongating RNA polymerase II (RNAPII) at DNA lesions blocks transcription and triggers transcription-coupled repair (TCR). However, the mechanisms determining the fate of stalled RNAPII remain incompletely understood. Here, we develop a time-resolved assay to track RNAPII clearance and degradation at UV-induced lesions. We show that RNAPII ubiquitylation by CSB and the CRL4CSA ubiquitin ligase is essential, as loss of these proteins causes persistent RNAPII accumulation at damage sites. Downstream of CSB/CRL4CSA-mediated ubiquitylation, two distinct pathways mediate RNAPII removal. The primary rapid route relies on TFIIH, with its XPD helicase activity driving RNAPII dissociation after proper recruitment and positioning by ELOF1, UVSSA, and STK19. A secondary slow pathway is mediated by the ubiquitin-dependent segregase VCP, which compensates for impaired TFIIH function. While VCP contributes only minimally in TCR-proficient cells, inhibition of VCP in TFIIH-deficient contexts completely abrogates RNAPII clearance. Together, these findings establish a hierarchical program in which CSB/CRL4CSA-mediated ubiquitylation initiates RNAPII processing, TFIIH/XPD helicase activity provides the main clearance mechanism, and VCP-dependent extraction acts as a backup when TFIIH fails. This mechanistic framework explains how cells resolve DNA lesion-stalled RNAPII during normal and compromised TCR.
    DOI:  https://doi.org/10.1038/s41467-026-68413-4
  6. Nat Commun. 2026 Jan 22.
    Evaluating single-cell ATAC-seq atlasing technologies using sequence-to-function modeling.
    Hannah Dickmänken, Marta Wojno, Lukas Mahieu, Koen Theunis, Eren Can Ekşi, Valerie Christiaens, Niklas Kempynck, Florian V De Rop, Natalie Roels, Katina I Spanier, Roel Vandepoel, Gert Hulselmans, Suresh Poovathingal, Stein Aerts.
      Deciphering the cis-regulatory logic underlying cell type identity remains a key challenge in biology. Single-cell chromatin accessibility (scATAC-seq) atlases enable training of sequence-to-function (S2F) deep learning models to decode enhancer logic. Yet, optimal criteria for constructing training datasets, i.e., the number of cells and ATAC fragments, remain unclear. Moreover, the suitability of different scATAC-seq platforms for such models has not been systematically tested. We introduce HyDrop v2, an improved custom droplet scATAC-seq method, and perform the first benchmark of scATAC-seq platforms focusing on its capacity to train S2F models and its capacity to yield TF footprints in different species. We show that lower fragment counts can be compensated for by increased cell numbers. S2F models trained on custom or commercial data perform comparably in enhancer prediction, sequence explainability, and transcription factor footprinting. We demonstrate that integrating data from different scATAC-seq platforms enables large-scale, cost-efficient atlas construction for deep learning-based regulatory modeling.
    DOI:  https://doi.org/10.1038/s41467-026-68742-4
  7. Genome Res. 2026 Jan 21. pii: gr.280436.125. [Epub ahead of print]
    Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease.
    Yunxiao Ren, Ming Hu, Yang E Li, Andrew A Pieper, Jeffrey Cummings, Feixiong Cheng.
      Alzheimer's disease (AD) is a complex and poorly understood neurodegenerative disorder that lacks sufficiently effective treatments. Computational and integrative analyses that leverage multiomics data provide a promising strategy to uncover disease mechanisms and identify therapeutic opportunities. Here, we develop a cell type-specific regulatory atlas of the human middle temporal gyrus via leveraging single-nucleus RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) datasets from 84 donors across four stages of AD neuropathological change (ADNC). We observe differential gene expression for six major cell types intensified at severe ADNC. Integrating peak-to-gene linkages and motif enrichment analyses, we reconstruct transcription factor (TF)-target gene networks across six major brain cell types. By integrating genome-wide association study (GWAS) loci with cell type-specific cis-regulatory DNA elements (CREs), we pinpoint 141 ADNC-associated genes. Using gene set enrichment analysis (GSEA) and network proximity analysis, we further identify nine candidate repurposable drugs that were associated with these ADNC-related genes. In summary, this cell type-specific multiomics atlas provides a comprehensive resource for mechanistic understanding, target prioritization, and therapeutic hypothesis generation in AD and AD-related dementia if broadly applied.
    DOI:  https://doi.org/10.1101/gr.280436.125
  8. Sci Adv. 2026 Jan 23. 12(4): eaeb6379
    Superenhancers shape the landscape and repair dynamics of transcription-associated DNA breaks in cancer.
    Osama Hidmi, Diala Shatleh, Sara Oster Flayshman, Jonathan Monin, Rami I Aqeilan.
      Cancer is characterized by uncontrolled proliferation accompanied by oncogene hypertranscription, leading to transcription stress, a key source of DNA double-strand breaks (DSBs) that jeopardize genomic stability. Despite its importance, the landscape and consequences of transcription stress remain underexplored. Here, we used maps of DSBs identified through sBLISS (in-suspension break labeling in situ and sequencing) with transcription stress markers to delineate the transcription stress landscape in cancer. We found that transcription stress sites are shaped by the superenhancer regulatory landscape. Notably, γH2AX is enriched at transcription stress sites; however, not all DSB-enriched genes show similar γH2AX marking. Instead, genes with DSBs tied to transcription stress are distinctly marked. Genes with high DSBs marked by γH2AX exhibited substantially higher DSB turnover and repair than those with low γH2AX, and are associated with vulnerability to mutagenesis. These findings underscore superenhancer activity as a determinant of the transcription stress landscape in cancer, posing a threat to the genomic stability of oncogenes.
    DOI:  https://doi.org/10.1126/sciadv.aeb6379
  9. Genome Biol. 2026 Jan 19.
    CLAMP: predicting specific protein-mediated chromatin loops in diverse species with a chromatin accessibility language model.
    Zhijie He, Yu Sun, Hao Li, Canzhuang Sun, Xianhui Yang, Hebing Chen, Mingzhi Liao, Xiaochen Bo.
      Emerging DNA language models provide powerful tools to address the challenge of accurately predicting chromatin loops, fundamental structures governing 3D genome organization and gene regulation. Here we present CLAMP, which utilizes a deep language model pre-trained on broad cross-species chromatin accessibility data. CLAMP achieves superior performance compared to existing methods in predicting specific protein-mediated loops across 10 species, 18 proteins, and 24 cell types. CLAMP incorporates a novel CoVE explainer that reveals context-dependent genomic feature contributions, providing insights into the features driving predictions. CLAMP predictions effectively identify functionally significant chromatin loops and associated biological pathways.
    Keywords:  3D Genome; Chromatin loops; Epigenomics; Language models
    DOI:  https://doi.org/10.1186/s13059-026-03948-9
  10. Nature. 2026 Jan 21.
    Critical role for a high-plasticity cell state in lung cancer.
    Jason E Chan, Chun-Hao Pan, Jonathan Rub, Gary Guzman, Klavdija Krause, Emma Brown, Zeda Zhang, Hannah Styers, Griffin Hartmann, Zhuxuan Li, Xueqian Zhuang, Scott W Lowe, Doron Betel, Yan Yan, Tuomas Tammela.
      Plasticity-the ability of cells to undergo phenotypic transitions-drives cancer progression and therapy resistance1-3. Recent studies have suggested that plasticity in solid tumours is concentrated in a minority subset of cancer cells4-6, yet functional studies examining this high-plasticity cell state (HPCS) in situ are lacking. Here we develop mouse models enabling the detection, longitudinal lineage tracing and ablation of the HPCS in autochthonous lung tumours in vivo. Lineage tracing reveals that the HPCS cells possess a high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and progressed lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals that HPCS-derived cells have a high capacity for growth compared with bulk cancer cells or another cancer cell state with features of differentiated lung epithelium. Ablation of HPCS cells in early neoplasias abrogates benign-to-malignant transition, whereas ablation in established tumours by suicide gene or chimeric antigen receptor (CAR) T cells robustly reduces tumour burden. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas HPCS ablation suppresses resistance to chemotherapy and oncoprotein-targeted therapy. Notably, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.
    DOI:  https://doi.org/10.1038/s41586-025-09985-x
  11. Mol Syst Biol. 2026 Jan 19.
    Pooled single-cell screen in colorectal cancer defines transcriptional modules linked to oncogenes.
    Viola Hollek, Francisca Böhning, Catalina Florez Vargas, Anja Sieber, Markus Morkel, Nils Blüthgen.
      Oncogenic mutations shape colorectal cancer (CRC) biology, yet their impact on transcriptional phenotypes remains incompletely understood, and their individual prognostic value is limited. Here, we perform a pooled single-cell transcriptomic screen of over 100,000 CRC cells with a comprehensive barcoded library of oncogenic variants across genetically diverse CRC lines. Using a variational autoencoder-based interpretable factor model, we identify ten conserved oncogene-driven transcriptional modules (TMOs) representing core cancer phenotypes such as cellular plasticity, inflammatory response, replicative stress, and epithelial-to-mesenchymal transition. Engagement of these modules can be context-dependent, reflecting interactions between oncogene-induced driver pathways and background genetics. TMO activity in patient tumors stratifies CRC cohorts into high- and low-risk groups, improving relapse-free survival prediction beyond existing classification systems. Our study systematically links oncogenic signaling to transcriptional states and clinical outcomes, establishing a functional framework for module-based patient stratification in precision oncology.
    Keywords:  Colorectal Cancer; Oncogenes; Signatures; Single Cell Screening; Transcriptional Modules
    DOI:  https://doi.org/10.1038/s44320-025-00186-2
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