bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2026–02–01
eight papers selected by
Connor Rogerson, University of Cambridge
  1. Structural basis of transcription-coupled H3K36 trimethylation by Set2 in coordination with FACT.
  2. NuMA promotes constitutive heterochromatin compaction by stabilizing linker histone H1 on chromatin.
  3. LDB1 regulates gene expression and chromatin structure in pluripotency and lineage differentiation.
  4. Advances in scCUT&Tag and computational analysis for single-cell gene regulatory element mapping.
  5. Zinc-finger transcription factor Fzf1 binds to its target DNA in a non-canonical manner.
  6. Advancing regulatory variant effect prediction with AlphaGenome.
  7. Scalable and multiplexed recorders of gene regulation dynamics across weeks.
  8. Dimerization-dependent gel-like condensation with dsDNA underpins the activation of human cGAS.
  1. Sci Adv. 2026 Jan 30. 12(5): eaed1952
    Structural basis of transcription-coupled H3K36 trimethylation by Set2 in coordination with FACT.
    Tomoya Kujirai, Haruhiko Ehara, Tomoko Ito, Masami Henmi, Eriko Oya, Takehiko Kobayashi, Shun-Ichi Sekine, Hitoshi Kurumizaka.
      Trimethylation of the histone H3K36 residue (H3K36me3) plays an indispensable role in ensuring transcription fidelity by suppressing undesired cryptic transcription in chromatin. H3K36me3 modification is accomplished by Set2/SETD2 during transcription elongation by the RNA polymerase II elongation complex (EC). Here, we found that Set2-mediated H3K36me3 deposition occurs on the nucleosome reassembling behind the EC. The histone chaperone FACT suppresses H3K36me3 deposition on the downstream nucleosome, thereby ensuring that Set2 targets specifically on the reassembling upstream nucleosome. Cryo-electron microscopy structures of the nucleosome-transcribing EC complexed with Set2 revealed that Set2 is anchored by the Spt6 subunit of the EC to capture both of the H3 N-terminal tails in a stepwise manner during the nucleosome reassembly process. Abrogation of the Set2-EC interaction leads to defective transcription-coupled H3K36me3 deposition. These insights elucidate the structure-based mechanism of transcription-coupled H3K36me3 deposition in chromatin.
    DOI:  https://doi.org/10.1126/sciadv.aed1952
  2. Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01673-0. [Epub ahead of print]45(2): 116901
    NuMA promotes constitutive heterochromatin compaction by stabilizing linker histone H1 on chromatin.
    Yao Wang, Wenxue Zhao, Jiahao Niu, Cuifang Liu, Xiaotian Wang, Weihong Yuan, Shanshan Ai, Wolfgang Baumeister, Guohong Li, Aibin He, Peng Xu, Cheng Li, Yujie Sun.
      Heterochromatin exerts pivotal functions of silencing specific genes and maintenance of genome stability. However, its formation and maintenance mechanisms remain unclear. Here, we discover that the mitotic regulator NuMA, as a nucleoskeleton protein, is required for constitutive heterochromatin organization at the nucleosome level in interphase. NuMA depletion results in shortened nucleosome repeat length, dispersed nucleosome clutches, increased chromatin accessibility, and disrupted transcription repression of long terminal repeats in heterochromatin regions. Such functions of NuMA rely on its interaction with linker histone H1, which stabilizes H1's binding to chromatin and facilitates nucleosome stacking, as directly visualized by in situ cryo-ET. Notably, NuMA oligomerizes into quasi-meshwork in the nucleoplasm, providing its organization basis as a nucleoskeleton protein. Collectively, our findings illuminate the concerted effect of nucleoskeleton and linker histone on chromatin compaction at the nucleosome level, unveiling a previously unexplored mechanism by which nucleoskeleton regulates heterochromatin formation and maintenance.
    Keywords:  CP: cell biology; CP: molecular biology; NuMA; constitutive heterochromatin; linker histone H1; nucleoskeleton; nucleosome stacking
    DOI:  https://doi.org/10.1016/j.celrep.2025.116901
  3. Nucleic Acids Res. 2026 Jan 22. pii: gkag064. [Epub ahead of print]54(3):
    LDB1 regulates gene expression and chromatin structure in pluripotency and lineage differentiation.
    HeungSun Kwon, Juhyun Kim, Lecong Zhou, Ann Dean.
      Chromatin organization is a pivotal factor in stem cell pluripotency and differentiation. However, the role of enhancer looping protein LIM domain-binding 1 (LDB1) in stem cells remains to be fully explored. We generated Ldb1(-/-) embryonic stem cells (ESCs) using CRISPR/Cas9 editing and observed a reduction in key stem cell factors SOX2 and KLF4 upon LDB1 loss. Differential gene expression, including of the Lin28-mediated self-renewal pathway genes, was observed between wild-type and Ldb1(-/-) ESC. LDB1 occupied super enhancers, including those of pluripotency genes, in ESC together with pluripotency factors, and LDB1 loss resulted in loss of Sox2 interactions with the SCR enhancer. Embryoid bodies (EBs) derived from Ldb1(-/-) ESC displayed reduced expression of lineage-specific markers. Ldb1(-/-) ESC had impaired ability to undergo terminal differentiation to erythroblasts, and gene dysregulation was very pronounced in Ldb1(-/-) erythroblasts. Conditional LDB1-deficient mice displayed reduced hematopoietic stem cell markers on bone marrow cells and dysregulation of the Lin28 pathway. Thus, LDB1 function is critical for ESC and EB development and becomes progressively more important for normal gene expression during differentiation to erythroblasts.
    DOI:  https://doi.org/10.1093/nar/gkag064
  4. Brief Bioinform. 2026 Jan 07. pii: bbag015. [Epub ahead of print]27(1):
    Advances in scCUT&Tag and computational analysis for single-cell gene regulatory element mapping.
    Jun Wu, Md Wahiduzzaman, Pengfei Yin, Puxuan Sun, Haoping Chen, Yongwen Ding, Jiankang Wang.
      Histone modifications (HMs) and transcription factors (TFs) are central to chromatin dynamics and transcriptional regulation. Conventional bulk approaches like ChIP-seq require large cell populations, limiting applicability to heterogeneous studies and tissue samples. In contrast, single-cell cleavage under targets and tagmentation (scCUT&Tag) and its variants have enabled high-resolution profiling of HMs and TFs for investigating gene regulatory mechanisms in individual cells, transformatively broadening single-cell epigenomics beyond chromatin accessibility measured by scATAC-seq. Despite rapid advances in scCUT&Tag-related methods and the accumulation of ~21 public datasets, a systematic overview of the current research status, especially the forefront of computational analysis and ensuing challenges, remains lacking. Here, we comprehensively overview current scCUT&Tag studies from a bioinformatics perspective. We catalog representative applications spanning diverse chromatin features, experimental designs, and data characteristics. We delineate a typical computational workflow from matrix generation to downstream functional annotations, emphasizing distinctions from scATAC-seq analysis, and highlighting critical analytical considerations. We extensively survey commonly used computational tools and key algorithms, compare analytical features between scCUT&Tag and scATAC-seq, and discuss major challenges in integrative analysis. This work provides a structured reference for understanding the current research landscape of scCUT&Tag and offers computational perspectives for researchers aiming to explore gene regulatory machinery at single-cell resolution.
    Keywords:  bioinformatics; computational analysis; scCUT&Tag; single-cell epigenomics; transcriptional regulation
    DOI:  https://doi.org/10.1093/bib/bbag015
  5. Nucleic Acids Res. 2026 Jan 22. pii: gkag054. [Epub ahead of print]54(3):
    Zinc-finger transcription factor Fzf1 binds to its target DNA in a non-canonical manner.
    Chaoqun Ma, Ying Du, Wei Xiao, Stanley A Moore.
      Saccharomyces cerevisiae Fzf1 is a transcriptional regulator with five Cys2His2 zinc fingers, controlling the expression of SSU1, YHB1, DDI2/3, and YNR064C genes through a shared promoter sequence CS2. After exposure to chemicals such as cyanamide (CY) or methyl methanesulfonate (MMS), Fzf1-regulated gene expression increases in yeast cells without concomitant changes in Fzf1 levels, suggesting that chemical modification of Fzf1 leads to increased transcription of target genes. Here, we showed that Fzf1 binds to the four known CS2 promoter sequences with comparable nanomolar affinity, while treatment of Fzf1 with inducing chemicals CY or MMS modestly increased its binding affinity for CS2 sequences. Crystallographic analysis of the N-terminal three zinc fingers of Fzf1 bound to a 26-bp YHB1 CS2 DNA containing the consensus sequence 3'-C3G4T5C6T7G8A9T10A11G12T13-5' reveals non-canonical recognition of duplex DNA for a zinc finger transcription factor. The first zinc finger interacts with the 5'-end dG3' of the standard non-recognition strand, while the second and third fingers read two (3'-T7G8-5') and four (3'-T10A11G12T13-5') adjacent base pairs on the recognition strand, respectively. Recognition of the DNA phosphodiester backbone by Fzf1 mostly resembles other zinc finger proteins. Future work will aim to elucidate how chemical modification of Fzf1 increases transcriptional activation in vivo.
    DOI:  https://doi.org/10.1093/nar/gkag054
  6. Nature. 2026 Jan;649(8099): 1206-1218
    Advancing regulatory variant effect prediction with AlphaGenome.
    Žiga Avsec, Natasha Latysheva, Jun Cheng, Guido Novati, Kyle R Taylor, Tom Ward, Clare Bycroft, Lauren Nicolaisen, Eirini Arvaniti, Joshua Pan, Raina Thomas, Vincent Dutordoir, Matteo Perino, Soham De, Alexander Karollus, Adam Gayoso, Toby Sargeant, Anne Mottram, Lai Hong Wong, Pavol Drotár, Adam Kosiorek, Andrew Senior, Richard Tanburn, Taylor Applebaum, Souradeep Basu, Demis Hassabis, Pushmeet Kohli.
      Deep learning models that predict functional genomic measurements from DNA sequences are powerful tools for deciphering the genetic regulatory code. Existing methods involve a trade-off between input sequence length and prediction resolution, thereby limiting their modality scope and performance1-5. We present AlphaGenome, a unified DNA sequence model, which takes as input 1 Mb of DNA sequence and predicts thousands of functional genomic tracks up to single-base-pair resolution across diverse modalities. The modalities include gene expression, transcription initiation, chromatin accessibility, histone modifications, transcription factor binding, chromatin contact maps, splice site usage and splice junction coordinates and strength. Trained on human and mouse genomes, AlphaGenome matches or exceeds the strongest available external models in 25 of 26 evaluations of variant effect prediction. The ability of AlphaGenome to simultaneously score variant effects across all modalities accurately recapitulates the mechanisms of clinically relevant variants near the TAL1 oncogene6. To facilitate broader use, we provide tools for making genome track and variant effect predictions from sequence.
    DOI:  https://doi.org/10.1038/s41586-025-10014-0
  7. Nature. 2026 Jan 26.
    Scalable and multiplexed recorders of gene regulation dynamics across weeks.
    Lirong Zheng, Dongqing Shi, Yixiao Yan, Bingxin Zhou, Jormay Lim, Yongjie Hou, Bobae An, Jason K Adhinarta, Michael Lin, BumJin Ko, William C Joesten, Mehul Gautam, Elie D M Huez, Eung Chang Kim, Emily G Klyder, Boxuan Chang, Sethuramasundaram Pitchiaya, Michael T Roberts, Denise J Cai, Edward S Boyden, Donglai Wei, Pietro Liò, Changyang Linghu.
      Gene expression is dynamically regulated by gene regulatory networks comprising multiple regulatory components to mediate cellular functions1. An ideal tool for analyzing these processes would track multiple-component dynamics with both spatiotemporal resolution and scalability within the same cells, a capability not yet achieved. Here, we present CytoTape, a genetically encoded, modular protein tape recorder for multiplexed and spatiotemporally scalable recording of gene regulation dynamics continuously for up to three weeks, physiologically compatible, with single-cell, minutes-scale resolution. CytoTape employs a flexible, thread-like, elongating intracellular protein self-assembly engineered via computationally assisted rational design, built on earlier XRI technology2. We demonstrated its utility across multiple mammalian cell types, achieving simultaneous recording of five transcription factor activities and gene transcriptional activities. CytoTape reveals that divergent transcriptional trajectories correlate with transcriptional history and signal integration, and that distinct immediate early genes (IEGs) exhibit complex temporal correlations within single cells. We further extended CytoTape into CytoTape-vivo for scalable, spatiotemporally resolved single-cell recording in the living brain, enabling simultaneous weeks-long recording of doxycycline- and IEG promoter-dependent gene expression histories across up to 14,123 neurons spanning multiple brain regions per mouse. Together, the CytoTape toolkit establishes a versatile platform for scalable and multiplexed analysis of cell physiological processes in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41586-026-10156-9
  8. Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01692-4. [Epub ahead of print]45(2): 116920
    Dimerization-dependent gel-like condensation with dsDNA underpins the activation of human cGAS.
    Jacob Lueck, Alexander Strom, Stephanie Martinez Torres, Shuai Wu, Jasper Moh, Hannah Wendorff, Brendan Antiochos, Jungsan Sohn.
      Cyclic G/AMP (cGAMP) synthase (cGAS) initiates inflammatory responses against pathogenic double-stranded (ds)DNA. Although it is well established that cGAS forms phase-separated condensates with dsDNA, its function remains poorly defined. We report here that the dimerization of cGAS on dsDNA creates a mesh-like network, leading to hydrogel-like condensate formation. While cGAS binds to and forms condensates with various nucleic acids, only dsDNA permits the dimerization necessary for activation and gelation. cGAS co-condenses dsDNA and other nucleic acids but retains a distinct dsDNA-mediated gel-like substate that can be dissolved by single-stranded RNA or short dsDNA. Moreover, compared with liquid-like condensates, we find that gel-like condensates are more effective not only in protecting bound dsDNA from exonucleases but also in limiting the mobility of nucleoside triphosphates and the dinucleotide intermediate for cGAMP synthesis. Together, our results show that enzymes can fine-tune surrounding microenvironments to regulate their signaling activities.
    Keywords:  CP: cell biology; CP: immunology; cGAS; condensates; gelation; innate immunity; phase separation; phase transition
    DOI:  https://doi.org/10.1016/j.celrep.2025.116920
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