bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2026–02–22
twenty-one papers selected by
Connor Rogerson, University of Cambridge
  1. Post-replicative chromatin accessibility predicts cell fate change.
  2. Engineering intrinsically disordered regions for guiding genome navigation.
  3. Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation.
  4. Z-DNA formation regulates the totipotent-like state and primes Zscan4-dependent chromatin compartmentalization.
  5. Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation.
  6. Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.
  7. Global reorganization of genome architecture at the transition to gametogenesis.
  8. Sequence bias in chromatin fragmentation leads to misinterpretation of protein-DNA interactions in vivo.
  9. Recruitment of BRD4 to the ASXL1 genomic targets depends on the extra-terminal domain of BRD4.
  10. Kinetic Model of E-P Condensates Dynamics Reveals Transcriptional Speed, Noise, Energy Trade-offs.
  11. NELF prevents transcriptional readthrough into DNA replication zones in cancer cells.
  12. Mapping and quantifying nascent transcript start sites using TT-TSS-seq.
  13. Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease.
  14. Trimodal single-cell profiling of transcriptome, epigenome and 3D genome in complex tissues with scHiCAR.
  15. SETDB1 enables development beyond cleavage stages by extinguishing the MERVL-driven two-cell totipotency transcriptional program in the mouse embryo.
  16. Trypanosome histone variants H3.V and H4.V promote nucleosome plasticity in repressed chromatin.
  17. Engineering chromatin loops to control cell fate: LoopID reveals catalytic-independent functions of epigenetic regulators.
  18. Modeling nascent transcription from chromatin landscape and structure with CLASTER.
  19. Gene body methylation buffers noise in gene expression in plants.
  20. Systematic analysis of functional genetic and epigenetic variants in colorectal cancer.
  21. Prevention of transgene silencing during human pluripotent stem cell differentiation.
  1. Stem Cell Reports. 2026 Feb 19. pii: S2213-6711(26)00032-9. [Epub ahead of print] 102821
    Post-replicative chromatin accessibility predicts cell fate change.
    Teresa E Knudsen, Nazaret Reverón-Gómez, Alva Biran, Nicolas Alcaraz, Sihem Cheloufi, Konrad Hochedlinger, Joshua M Brickman, Anja Groth, Kathleen R Stewart-Morgan.
      It has long been hypothesized that DNA replication is important in reconfiguring the chromatin landscape during cell identity changes in development, disease, and reprogramming. There is now a large body of work showing that DNA replication indeed alters chromatin structure and composition, but a function for these changes has remained elusive. Using replication-coupled ATAC-seq in differentiating embryonic stem cells and reprogramming mouse embryonic fibroblasts, we profiled replicated and unreplicated chromatin and observed de novo chromatin opening specifically in the replicated fraction. These opening events created an accessibility landscape similar to that seen in later time points, and binding of lineage-specific transcription factors was enriched in these regions. Opening of these regions was impaired when replication was inhibited during early reprogramming. This work bridges the gap between replication-induced structural chromatin changes and functional consequences by demonstrating that replication facilitates a "window of opportunity" that advances the chromatin landscape during cell identity change.
    Keywords:  DNA replication; cell fate change; chromatin accessibility; differentiation; repli-ATAC-seq; reprogramming; transcription factor binding
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102821
  2. Mol Cell. 2026 Feb 16. pii: S1097-2765(26)00061-4. [Epub ahead of print]
    Engineering intrinsically disordered regions for guiding genome navigation.
    Jing Liu, Divya Krishna Kumar, Bohdana Hurieva, Felix Jonas, Naama Barkai.
      Intrinsically disordered regions (IDRs) navigate transcription factors (TFs) to their binding sites in genomes, raising the question of how IDR sequences can encode for specific genome recognition. To define the principles of IDR-directed binding, we designed de novo IDRs and tested their activity in directing selective binding across the budding yeast genome. Our de novo IDRs were designed by dispersing hydrophobic amino acids within hundreds of hydrophilic residues, as we found to be required in native TF-directing IDRs. Although showing no alignment-based similarity to native TFs, the de novo IDRs were active in directing genome binding toward a tunable range of targets, as revealed by systematically varying the hydrophobic spread or disorder scaffold. Overall, the 185 synthetic IDRs tested displayed a continuum of sequence-directed binding preferences across hundreds of promoters. Our results open new doors for understanding and engineering selective binding across genomes.
    Keywords:  ChEC-seq; gene regulation; intrinsically disordered regions; synthetic biology; transcription factors
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.019
  3. Nat Commun. 2026 Feb 14.
    Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation.
    Aleksandra Galitsyna, Sergey V Ulianov, Mariia Bazarevich, Nikolai S Bykov, Marina Veil, Meijiang Gao, Kristina Perevoschikova, Mikhail S Gelfand, Sergey V Razin, Leonid Mirny, Daria Onichtchouk.
      The initiation of gene expression during development, known as zygotic genome activation (ZGA), is accompanied by massive changes in chromosome organization. However, the earliest events of chromosome folding and their functional roles remain unclear. Using Hi-C on zebrafish embryos, we discovered that chromosome folding begins early in development with the formation of fountains, distinct elements of chromosome organization. Emerging preferentially at enhancers, fountains show an initial accumulation of cohesin, which later redistributes to CTCF sites at TAD borders. Knockouts of pioneer transcription factors driving ZGA enhancers cause a specific loss of fountains, establishing a causal link between enhancer activation and fountain formation. Polymer simulations demonstrate that fountains may arise as sites of facilitated cohesin loading, requiring two-sided but desynchronized loop extrusion, potentially caused by cohesin collisions with obstacles or internal switching. Moreover, we detected cohesin-dependent fountain patterns at enhancers in mouse cells and found them reemerging with cohesin loading after mitosis. Altogether, fountains represent enhancer-specific elements of chromosome organization and suggest that chromosome folding during development and after cell division starts with facilitated cohesin loading. Observations in multiple systems further support facilitated loading at enhancers as a widespread phenomenon.
    DOI:  https://doi.org/10.1038/s41467-026-69105-9
  4. Nat Struct Mol Biol. 2026 Feb 17.
    Z-DNA formation regulates the totipotent-like state and primes Zscan4-dependent chromatin compartmentalization.
    Shireen Shajahan, Yann Loe-Mie, Laure Asselin, Marion Salmon-Legagneur, Tatiana Traboulsi, Agnès Thierry, Anne Dejean, Jack-Christophe Cossec.
      The progression from the one-cell to the two-cell stage constitutes a remarkable transition, accompanied by the activation of a specific set of embryonic genes, epigenome reprogramming and nuclear architecture reorganization. Some of these characteristics are recapitulated in vitro with the spontaneous emergence of two-cell-like cells from mouse embryonic stem cells, which exhibit a transcriptomic signature resembling the two-cell stage, including the expression of genes such as Dux, Zscan4 and the repetitive element MERVL, as well as a more relaxed chromatin state. Here we show that interchromosomal and intrachromosomal interactions driven by Zscan4 chromatin factors form during this transition and segregate into a distinct genomic compartment, the Z compartment, independently of cohesin and CCCTC-binding factor. Mechanistically, the formation of Z-DNA, an alternative DNA conformation regulated by polyamine levels, appears to promote the emergence of totipotent-like cells and the establishment of the Z compartment. This compartment is characterized by a decrease in active histone marks and a reduced expression of genes associated with differentiation and late developmental processes. Overall, these findings suggest that Z-DNA formation may have a dual role, first in initiating zygotic genome activation (ZGA) and later in guiding genome compartmentalization to safeguard the totipotent-like state by restricting the expression of non-ZGA genes within a permissive chromatin environment.
    DOI:  https://doi.org/10.1038/s41594-026-01751-5
  5. Nat Genet. 2026 Feb 16.
    Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation.
    Tessa M Popay, Ami Pant, Femke Munting, Melodi Tastemel, Morgan E Black, Nicholas Haghani, Jesse R Dixon.
      The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here we utilized acute depletion of NIPBL to characterize cohesin-mediated loop extrusion in vivo. We find that many chromatin loops are rapidly diminished upon loss of NIBPL, but some cohesin-dependent chromatin loops persist for multiple hours. These persistent loops required NIPBL for their establishment during mitotic exit, were associated with distinct chromatin states and were preferentially dependent on STAG1 for their persistence. Furthermore, by depleting NIPBL from multiple cell types, we find that NIPBL specifically regulates cell identity genes by supporting a unique local genome conformation defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.
    DOI:  https://doi.org/10.1038/s41588-026-02516-y
  6. Nat Commun. 2026 Feb 21.
    Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.
    Richa Singh, Varadha Balaji Venkadakrishnan, Eddie Imada, Yasutaka Yamada, Nicholas J Brady, Kate E Dunmore, Richard Garner, Matthew A Booker, Brian Hanratty, Michael C Haffner, Michael Y Tolstorukov, Luigi Marchionni, Brian D Robinson, David S Rickman, Himisha Beltran.
      Prostate cancer lineage plasticity is associated with changes in DNA methylation and enhancer of zeste homolog 2 (EZH2) activity. How these epigenetic programs functionally interact to modulate transcriptional reprogramming in neuroendocrine prostate cancer (NEPC) is not well understood. In this study, we demonstrate that hypomethylated regions of DNA preferentially accumulate the repressive mark, H3K27me3. We established an NEPC mouse model with deletion of Ezh2 in the background of Pten and Rb1 loss plus human MYCN overexpression. Deletion or pharmacological inhibition of EZH2 in NEPC murine or patient-derived models leads to a genome-wide rewiring of DNA methylation, characterized by hypomethylation and upregulation of neuroendocrine-lineage genes along with hypermethylation and repression of polycomb repressive complex 2 (PRC2) targets. On the other hand, deletion of DNA methyltransferase 1 (DNMT1) results in significant changes in H3K27me3 distribution, particularly affecting bivalent promoters bearing both H3K27me3 and active H3K4me3 marks. In NEPC models, neuroendocrine-lineage genes are repressed upon DNMT1 deletion associated with increased H3K27me3. Conversely, in prostate adenocarcinoma models, DNMT1 deletion leads to de-repression of neuroendocrine lineage genes with a loss of H3K27me3 marks. Our findings reveal a functional interplay between two repressive epigenetic machineries that mediates lineage plasticity in prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-026-69308-0
  7. Nat Struct Mol Biol. 2026 Feb 20.
    Global reorganization of genome architecture at the transition to gametogenesis.
    Tien-Chi Huang, Maria Rigau, Valeriya Malysheva, Chad Whilding, Stella Siciliani, Jingyu Li, Irina Balaguer Balsells, Pavel Artemov, Camille Dion, Mikhail Spivakov, Juan M Vaquerizas, Petra Hajkova.
      Global epigenetic resetting in the gonadal primordial germ cells (PGCs) enables transition from early PGCs to gametogenesis and eventual restoring of totipotency after fertilization. This reprogramming process involves global DNA demethylation, changes in nuclear morphology and remodeling of repressive histone modifications. Here, using combined cytological and Hi-C-based methods, we reveal that, following the epigenetic reprogramming and concomitant with their commitment to gametogenesis, premeiotic gonadal germ cells display a distinct chromosome and genome architecture. This involves separation of individual chromosomes, anchoring of centromeres at the nuclear periphery, reduction in interchromosome interactions and disentangling of chromosome ends. Furthermore, genome-wide contact mapping documents remodeling of the three-dimensional (3D) genome architecture across all observable levels, including disruption of topologically associating domains (TADs), loss of detectable loops and reduced active-active compartment interactions. We further show that the diminished TADs correlate with the reduced levels of CCCTC-binding factor, thus providing an in vivo physiological model to understand genome folding principles. Lastly, we show that PGC-like cells, derived from embryonic stem cells, do not exhibit the same chromatin organization as embryonic germ cells. Collectively, our findings uncover the existence of a distinct chromatin architecture in premeiotic male and female gonadal germ cells and show that, alongside global DNA demethylation, the germline epigenetic reprogramming involves erasure of memory at the genome architectural level through profound reorganization of the 3D genome.
    DOI:  https://doi.org/10.1038/s41594-026-01747-1
  8. Genome Biol. 2026 Feb 16.
    Sequence bias in chromatin fragmentation leads to misinterpretation of protein-DNA interactions in vivo.
    Laura Durán, Laura Rodríguez, Alicia García, Rodrigo Santamaría, Mar Sánchez, Francisco Antequera.
      Genome regulation depends on the binding of regulatory proteins to chromatin. V-plots are widely used to assess the binding of transcription factors and other protein complexes to DNA in vivo. However, we show here that V-plots result from the cleavage sequence preferences of the chromatin fragmentation methods and can be generated equally well on naked deproteinised DNA as on chromatin, and on any randomly selected sequence motif in the genome. Our results argue against using chromatin fragmentation methods, combined to previous knowledge of motifs as the only method to map DNA-associated proteins by stacking the end of sequence reads over genomic regions that share a common nucleotide motif.
    DOI:  https://doi.org/10.1186/s13059-026-04004-2
  9. Nat Commun. 2026 Feb 17.
    Recruitment of BRD4 to the ASXL1 genomic targets depends on the extra-terminal domain of BRD4.
    Karthik Selvam, Shuang Lu, Clémence Messmer, Yakun Pang, Soumi Biswas, Moustafa Khalil, Peng Zhang, Rima Tulaiha, Ming-Ming Zhou, Toshio Kitamura, Shannon M Lauberth, M Andres Blanco, Feng-Chun Yang, El Bachir Affar, Zibo Zhao, Lei Zeng, Lu Wang, Tatiana G Kutateladze.
      ASXL1 is a well-established driver of a wide range of cancers. Here, we identify a high level of genetic correlation between ASXL1 and the major transcriptional activator BRD4 in cancer cells and characterize the molecular mechanism underlying this correlation. Structural and biochemical data show the formation of a tight complex between the extraterminal domain of BRD4 and the BRD4-binding motif of ASXL1. ChIP-seq analysis of mutated ASXL1 that cannot bind BRD4 demonstrates that the recruitment of BRD4 to the ASXL1 genomic targets depends on this interaction. We find that the cancer-related truncated variants comprising residues 1-645 and 1-591 of ASXL1 (ASXL11-645 and ASXL11-591) retain BRD4 binding function, with ASXL11-645 showing an enhanced ability to recruit BRD4 to promoters of ASXL1 target genes. In contrast to ASXL11-591, ASXL11-645 simultaneously and independently interacts with BRD4 and the H3K4-specific methyltransferases MLL3/4, whereas the shorter variant is lacking the MLL3/4-binding site and interacts only with BRD4. Genomic data from six cancer types reveals a strong positive ASXL1-BRD4 relationship, with BRD4 occupying the ASXL1 promoter and thus pointing to a possible feed-forward mechanism. Our findings provide mechanistic details by which ASXL1 associates with BRD4 and shed light on the biological significance of this association.
    DOI:  https://doi.org/10.1038/s41467-026-69565-z
  10. Biophys J. 2026 Feb 17. pii: S0006-3495(26)00135-9. [Epub ahead of print]
    Kinetic Model of E-P Condensates Dynamics Reveals Transcriptional Speed, Noise, Energy Trade-offs.
    Swayamshree Senapati, Ajeet K Sharma, Hemant Kumar.
      Gene regulation emerges from the interplay between chromatin architecture and the molecular interactions that connect enhancers to promoters. To study how these interactions shape transcriptional dynamics, we developed a kinetic model that incorporates multivalent enhancer-promoter binding, transcription factor competition, steric constraints, and chromatin accessibility. The model shows that competition among regulatory factors can generate bistable promoter states at the expense of increased transcriptional noise, revealing a direct relationship between bistability and noise levels. It further predicts that promoter response times are fastest in parameter regimes where bistability appears, suggesting that regulatory dynamics supporting two promoter states may intrinsically enable rapid activation. Extending this analysis, we find that intermediate chromatin accessibility and competition between activators and repressors both promote bistable enhancer-bound promoter clusters and fast switching at the cost of higher noise, whereas very high or low accessibility and noncompetitive transcription factors result in monostable expression states. The model also offers a quantitative framework to compare the energetic costs of different regulatory strategies, indicating that under energy constraints, cells may favor adjusting transcription factor concentrations rather than altering chromatin accessibility, thereby linking energy expenditure to regulatory flexibility and robustness.
    DOI:  https://doi.org/10.1016/j.bpj.2026.02.015
  11. EMBO Rep. 2026 Feb 20.
    NELF prevents transcriptional readthrough into DNA replication zones in cancer cells.
    Chihiro Nakayama, Qi Fang, Yasukazu Daigaku, Yuki Aoi, Shoko Ito, Mami Takahashi, Reo Shimatani, Tamiko Minamisawa, Yagiz Ozturk, Hiroshi Kimura, Ali Shilatifard, Michael Tellier, Takayuki Nojima.
      Regulation of RNA polymerase II (Pol II) transcription is closely associated with cell proliferation. However, it remains unclear how the Pol II transcription program is rewired in cancer to promote uncontrolled growth. Here, we find that expression of NELFCD, a known negative transcription elongation factor, is upregulated in colorectal tumors. Auxin-dependent protein degradation of NELF-C in combination with nascent transcript sequencing demonstrates a direct role of NELF-C on Pol II transcription in this cancer. Strikingly, we demonstrate that the acute loss of NELF-C protein globally redistributes termination factors and perturbs Pol II transcription termination. These changes drive pervasive Pol II transcription into DNA replication zones, leading to transcription-replication conflict that may block the cell cycle in G1 or early S phase. Our findings reveal a previously unrecognized role of NELF in transcription termination and highlight NELF as a potential therapeutic target in colorectal cancer.
    Keywords:  DNA Replication; NELF; RNA Polymerase II; Transcription Termination; Transcription-replication Conflict
    DOI:  https://doi.org/10.1038/s44319-026-00700-z
  12. Genome Res. 2026 Feb 17.
    Mapping and quantifying nascent transcript start sites using TT-TSS-seq.
    Eleanor Elgood Hunt, Claudia Vivori, Richard Mitter, Vedis Agnadottir, Folkert J van Werven.
      Transcription initiation is a highly dynamic and tightly regulated process involving the coordinated action of transcription factors, chromatin remodelers, and RNA polymerase, which determine where and when transcription begins. Accurately mapping and quantifying transcription start sites (TSSs) from nascently transcribed RNAs remains a key area of interest, as it provides critical insights into transcription dynamics. Here, we combine transient transcriptome sequencing with transcription start site sequencing (TT-TSS-seq) to accurately map and quantify transcription initiation sites from nascent transcripts. Because transient metabolic labeling yields low-input RNA, we optimize the TSS-seq protocol to enhance sensitivity and accuracy. Specifically, we refine enzymatic reactions for decapping and RNA ligation and incorporate 5' oligonucleotides containing unique molecular identifiers (UMIs) and barcodes to enable accurate quantification and sample multiplexing. The TT-TSS-seq approach detects transcription initiation of unstable transcripts, such as enhancer RNAs. Moreover, we show that a large fraction of genes use multiple transcription initiation sites, yet often produce only a single stable transcript. Overall, TT-TSS-seq provides precise mapping and quantification of transcription initiation sites, offering new insights into transcriptional dynamics and expanding the toolkit for studying gene regulation.
    DOI:  https://doi.org/10.1101/gr.280726.125
  13. Nat Commun. 2026 Feb 18.
    Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease.
    Jiuwei Lu, Emily Vig, Jianbin Chen, Kristjan H Gretarsson, Nelli Khudaverdyan, Zengyu Shao, Chao Lu, Chia-En A Chang, Jikui Song.
      DNA methyltransferase DNMT3A-mediated DNA methylation is important for genomic imprinting and transcriptional regulation. However, how the regulatory domains of DNMT3A cooperate with its methyltransferase domain and histone marks to orchestrate genomic methylation remains unclear. Here we report the cryo-EM structure of DNMT3A2 with regulatory factor DNMT3L, revealing an intricate domain interaction underlying multilayered autoinhibition. The PWWP domain interacts with the ADD and methyltransferase domains to block the target recognition domain and the H3K36me2-binding pocket, thereby coupling the H3K36me2 binding with DNMT3A activation, adding a layer of allosteric regulation distinct from the previously characterized ADD-H3K4me0 regulation. Molecular dynamics simulations of the DNMT3A-DNMT3L complex further reveals that relief of DNMT3A autoinhibition involves disengagement of the CpG-recognition loop of the target recognition domain from autoinhibitory interaction, leading to enhanced accessibility of the target recognition domain loop for DNA binding and DNMT3A activation. Importantly, our combined structural, biochemical and genomic methylation analysis demonstrates that disrupting the PWWP-ADD interaction by disease-associated DNMT3A mutations leads to impaired DNMT3A autoinhibition and substrate specificity, providing a potential explanation to aberrant DNA methylation in disease.
    DOI:  https://doi.org/10.1038/s41467-026-69563-1
  14. Nat Biotechnol. 2026 Feb 19.
    Trimodal single-cell profiling of transcriptome, epigenome and 3D genome in complex tissues with scHiCAR.
    Xiaolin Wei, Yueyuan Xu, Dongchan Yang, Kyukwang Kim, Lizhi Yi, Wenzhe Luo, Xin Lin, Yu Xiang, Ashley B Williams, Xiaotao Wang, Sweta Srivas, Christabel Tan, Kan Zhang, Wei Li, Yang Eric Li, Feng Yue, Z Josh Huang, Inkyung Jung, Yarui Diao.
      The three-dimensional (3D) organization of cis-regulatory elements (CREs) is critical in transcription control. However, capturing transcriptome, epigenome and 3D genome from the same single cells remains challenging. Here we present scHiCAR (single-cell Hi-C with assay for transposase-accessible chromatin and RNA sequencing), a plate-based combinatorial barcoding method that simultaneously profiles mRNA, open chromatin and chromosome conformation capture from the same cells. Compared to existing single-cell 3D genome methods, scHiCAR more efficiently enriches long-range cis-interactions anchored at candidate CREs (cCREs). Applied to 1.62 million mouse brain cells and complemented with a deep-learning-based loop caller, scHiCAR accurately defines cell-type-specific transcriptomes, accessible cCREs and 5-kb-resolution enhancer-promoter pairs across 22 brain cell types. scHiCAR also performs robustly in challenging tissues such as skeletal muscle, enabling trimodal single-cell-level analysis of gene regulation dynamics during muscle stem cell regeneration. By providing a scalable and cost-effective system for single-cell trimodal analysis of gene-regulatory landscapes in complex tissues, scHiCAR reveals gene-locus-specific regulatory roles of 3D genome reorganization in transcriptional control.
    DOI:  https://doi.org/10.1038/s41587-026-03013-7
  15. Elife. 2026 Feb 16. pii: RP109248. [Epub ahead of print]15
    SETDB1 enables development beyond cleavage stages by extinguishing the MERVL-driven two-cell totipotency transcriptional program in the mouse embryo.
    Tie-Bo Zeng, Zhen Fu, Mary F Majewski, Ji Liao, Marie Adams, Piroska E Szabó.
      Loss of maternal SETDB1, a histone H3K9 methyltransferase, leads to developmental arrest prior to implantation, with very few mouse embryos advancing beyond the eight-cell stage, which is currently unexplained. We genetically investigate SETDB1's role in the epigenetic control of the transition from totipotency to pluripotency-a process demanding precise timing and forward directionality. Through single-embryo total RNA sequencing of two-cell and eight-cell embryos, we find that Setdb1mat-/+ embryos fail to extinguish one-cell and two-cell transient genes-alongside persistent expression of MERVL retroelements and MERVL-driven chimeric transcripts that define the totipotent state in mouse two-cell embryos. Comparative bioinformatics reveals that SETDB1 acts at MT2 LTRs and MERVL-driven chimeric transcripts, which normally acquire H3K9me3 during early development. The dysregulated targets substantially overlap with DUXBL-responsive genes, indicating a shared regulatory pathway for silencing the two-cell transcriptional program. We establish maternal SETDB1 as a critical chromatin regulator required to extinguish retroelement-driven totipotency networks and ensure successful preimplantation development.
    Keywords:  MERVL; SETDB1; genetics; genomics; maternal effect; mouse; preimplantation; single embryo total RNAseq; totipotency
    DOI:  https://doi.org/10.7554/eLife.109248
  16. Structure. 2026 Feb 17. pii: S0969-2126(26)00010-9. [Epub ahead of print]
    Trypanosome histone variants H3.V and H4.V promote nucleosome plasticity in repressed chromatin.
    Gauri Deák, Hayden Burdett, James A Watson, Marcus D Wilson.
      Histone variants define distinct chromatin states by modulating the biophysical properties of nucleosomes. Variants play a particularly important role in the parasitic protist Trypanosoma brucei, which has unusual chromatin and lacks a canonical repressive heterochromatin system. Instead, T. brucei utilizes specialized divergent histone variants H3.V and H4.V. However, the biochemical basis of their repressive functions is unknown. Here, we determined the structure of the H3.V-H4.V nucleosome core particle and biochemically characterized variant-containing nucleosomes and nucleosome arrays, probing their unique properties. We discovered that surprisingly for repressive-state nucleosomes, H3.V promotes pronounced DNA splaying, largely via its N-terminal tail region, while retaining overall stability that is comparable to canonical nucleosomes. In contrast, H4.V exhibits near-identical binding to DNA but mediates a slight increase in histone octamer stability. The surface of the H3.V-H4.V nucleosome is altered and provides a differential platform for chromatin-binding proteins, linking the variants to parasite pathogenicity.
    Keywords:  chromatin; cryo-EM; heterochromatin; histone variants; kinetoplastid; nucleosome; parasite; trypanosome
    DOI:  https://doi.org/10.1016/j.str.2026.01.008
  17. Cell Transplant. 2026 Jan-Dec;35:35 9636897261424577
    Engineering chromatin loops to control cell fate: LoopID reveals catalytic-independent functions of epigenetic regulators.
    Huanhuan Li, José C R Silva.
      Enhancer-promoter (E-P) interactions are central to cell-type-specific transcriptional programs, yet the molecular machinery that establishes and maintains these loops has remained poorly defined. A recent study by Jiang et al, published in Nature Genetics, presents a series of transformative discoveries that redefine our understanding of E-P interactions and their role in gene regulation and cell fate determination. The research introduces LoopID, a chromatin-interaction-based proteomic platform that, for the first time, enables systematic identification of protein components, termed the "looposome," localized specifically at chromatin looping anchors. Using LoopID, they profile the "looposome" in mouse embryonic stem cells (ESCs) and uncover an unexpected, catalytic-independent role for the histone demethylase JMJD2 (KDM4) in organizing chromatin architecture through phase-separated condensates. Beyond mechanism, the study demonstrates that targeted assembly of JMJD2 condensates at defined genomic loci can engineer E-P interactions driving cellular reprogramming toward pluripotent and two-cell-like states. Together, these findings represent not only a major technical advance but also a conceptual leap-establish LoopID as a foundational technology for dissecting chromatin structure, introduce a new conceptual framework for epigenetic regulators as structural organizers, and provide a powerful strategy to manipulate cell fate by rewiring three-dimensional (3D) genome architecture.
    Keywords:  3D genome; LoopID; enhancer-promoter; looping; looposome
    DOI:  https://doi.org/10.1177/09636897261424577
  18. Genome Biol. 2026 Feb 14.
    Modeling nascent transcription from chromatin landscape and structure with CLASTER.
    Marc Pielies Avellí, Arnór Ingi Sigurdsson, Joaquim Ollé López, Takeo Narita, Nils Krietenstein, Chunaram Choudhary, Simon Rasmussen.
      We present the Chromatin Landscape and Structure to Expression Regressor (CLASTER), an epigenetic-based deep neural network that can integrate different data modalities describing the chromatin landscape and its 3D structure. CLASTER effectively translates them into nascent transcription levels measured at a kilobasepair resolution. The model provides a platform to understand the epigenetic drivers and learned rules of nascent transcription, and to predict the impact of in silico epigenetic perturbations. We conclude that the predominant locality of current machine learning approaches emerges as a signature of genomic organization, having broad implications for future modeling approaches.
    Keywords:  Chromatin landscape; Chromatin structure; Deep neural networks; EU-seq; Nascent transcription
    DOI:  https://doi.org/10.1186/s13059-026-03992-5
  19. Nucleic Acids Res. 2026 Feb 05. pii: gkag127. [Epub ahead of print]54(4):
    Gene body methylation buffers noise in gene expression in plants.
    Jakub Zastąpiło, Robyn A Emmerson, Liudmila A Mikheeva, Marco Catoni, Ulrike Bechtold, Nicolae Radu Zabet.
      Non-genetic variability in gene expression is an inevitable consequence of the stochastic nature of processes driving transcription and translation. While previous studies demonstrated that gene expression noise is negatively correlated with gene body methylation, the function of this correlation remains poorly understood in multicellular systems. Here, we provide a first functional link between gene body methylation and transcription noise in plants. We investigated a mutant with partial loss of CG methylation (met1-1) and 10 epigenetic recombinant inbred lines (epiRILs) generated by a cross between Col-0 and met1-3 plants, and observed an increase in gene expression noise, but this was not the case in met1-3 with complete loss of CG methylation. Loss of CG methylation in met1-3 could be compensated by a low but significant gain of non-CG methylation that buffers the noise in gene expression. Overall, our results show that gene body methylation has a functional role in reducing variability in transcription in a large subset of housekeeping genes, which require precise expression patterns to meet metabolic requirements. Genes lacking this noise-buffering effect are mainly enriched in stress response, where variability in gene expression can be seen as highly beneficial.
    DOI:  https://doi.org/10.1093/nar/gkag127
  20. Sci Adv. 2026 Feb 20. 12(8): eaeb2473
    Systematic analysis of functional genetic and epigenetic variants in colorectal cancer.
    Erfei Chen, Qiqi Yang, Haoyang Dai, Yixin Chen, Yihui Zhang, Qianglong Wang, Rongrong Hou, Ming Chen, Jie Wang, Qianwen Xie, Wenju Sun, Yong-Qiang Ning, Ligang Fan, Jian Yan.
      Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, yet the functional impact of noncoding variants on enhancer activity remains largely unexplored. In this study, we adapted and applied two high-throughput techniques, SNP-STARR-seq and Methyl-STARR-seq, to systematically evaluate the influence of 30,790 noncoding SNPs and more than 134,000 CpG sites on enhancer activity in primary and metastatic CRC cells. We identified 922 SNPs and 487 CpG-containing elements modulating enhancer activity in primary cells and found 3136 SNPs and 3008 methylation-sensitive elements with metastasis-specific regulatory effects. Multi-omics integration linked these variants to target genes, and CRISPR editing validated their roles in driving tumorigenic and metastatic phenotypes. Furthermore, we identified two CRC-specific hypermethylated loci, cg08640619 and cg25982657, as exceptional tissue-based early detection biomarkers (AUC > 0.96). Mechanistically, hypermethylation at cg08640619 disrupts RUNX2 binding, leading to inhibition of KIRREL1 and ETV3. Our study provides a comprehensive platform for understanding how genetic and epigenetic variants disrupt transcriptional programs in CRC, offering insights into disease susceptibility and identifying potential diagnostic and therapeutic targets.
    DOI:  https://doi.org/10.1126/sciadv.aeb2473
  21. Cell Stem Cell. 2026 Feb 13. pii: S1934-5909(26)00030-5. [Epub ahead of print]
    Prevention of transgene silencing during human pluripotent stem cell differentiation.
    Takeshi Uenaka, Alan Napole, Aninda Dibya Saha, Duo Sun, Angelina Singavarapu, Elizabeth Calzada, Jiahui Chen, Lena Erlebach, Amanda McQuade, Daniel M Ramos, Alessandra Rigamonti, Lisa Salazar, Avi J Samelson, Kamilla Sedov, Natalie J Welsh, Katleen Wild, Qianxin Wu, Ernest Arenas, Andrew R Bassett, Martin Kampmann, Deborah Kronenberg-Versteeg, Florian T Merkle, Birgitt Schüle, Leslie M Thompson, William C Skarnes, Michael E Ward, Marius Wernig.
      Transgenes are often silenced upon differentiation of pluripotent stem cells using conventional expression systems. Here, we developed the TK4 PiggyBac vector to conduct a comparative analysis to evaluate the impact of various promoters, transcriptional regulatory elements, insulators, and genomic integration sites on transgene silencing during neuronal differentiation. Our findings reveal that specific combinations of CAG and Ubc promoters with the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) can prevent transgene silencing during differentiation, whereas chromatin insulators have less impact on sustained expression. Three novel safe harbor loci, distant from known genes, as well as the citrate lyase beta-like (CLYBL) locus, similarly support the prevention of transgene silencing. Remarkably, the TK4 vector showed complete resistance to silencing across various neuronal and microglial differentiation protocols, as independently confirmed by seven laboratories. This construct will be highly useful for assays requiring stable transgene expression during differentiation and holds potential for broad applications in various research fields.
    Keywords:  PiggyBac vector; UCOE; WPRE; chromatin insulator; human pluripotent stem cells; microglia; neuron; promoter activity; safe harbor locus; transgene silencing; ubiquitous chromatin opening element; woodchuck hepatitis posttranscriptional regulatory element
    DOI:  https://doi.org/10.1016/j.stem.2026.01.007
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