bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–10–12
eight papers selected by
Connor Rogerson, University of Cambridge
  1. HDAC2-mediated recruitment of METTL3 to chromatin regulates human embryonic stem cell differentiation.
  2. Reporter CRISPR screens decipher cis-regulatory and trans-regulatory principles at the Xist locus.
  3. IceQream: Quantitative chromosome accessibility analysis using physical TF models.
  4. Fosl2 facilitates chromatin accessibility to determine developmental events during follicular maturation.
  5. HAND2 invades nucleolar condensates to pioneer lineage-specific cardiac pacemaker gene programs.
  6. Cisformer: a scalable cross-modality generation framework for decoding transcriptional regulation at single-cell resolution.
  7. Ultra-fast variant effect prediction using biophysical transcription factor binding models.
  8. Integrative chromatin state annotation of 234 human ENCODE4 cell types using Segway.
  1. Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01185-4. [Epub ahead of print]44(10): 116414
    HDAC2-mediated recruitment of METTL3 to chromatin regulates human embryonic stem cell differentiation.
    Jie Yang, Yikang Yang, Xiafei Zhang, Chenchao Yan, Liwen Jiang, Donghui Zhang, Wei Jiang.
      N6-methyladenosine (m6A) modification and its methyltransferase METTL3 are crucial for pluripotency maintenance and early development, but the underlying mechanism is largely unclear. Here, we demonstrate that METTL3 directly interacts with the histone deacetylase HDAC2 in chromatin. HDAC2 knockout reduces METTL3 chromatin binding and m6A levels on HDAC2 target genes linked to lineage differentiation, whereas METTL3 deletion does not affect HDAC2 expression or histone acetylation. Knocking out either HDAC2 or METTL3 significantly impairs human embryonic stem cell differentiation. We further observe that genes with reduced m6A upon depletion of HDAC2 exhibit decreased RNA stability and translation, mediated by the m6A readers IGF2BPs and YTHDC2, respectively. Mechanistically, HDAC2 recruits METTL3 to mediate m6A deposition on target genes and regulate RNA stability and translation, thereby modulating stem cell lineage differentiation. These findings identify a functional interactor of METTL3 and clarify the role of the HDAC2-METTL3 axis in human ESCs.
    Keywords:  CP: Molecular biology; CP: Stem cell research; HDAC2; METTL3; human embryonic stem cell; lineage differentiation; m6A
    DOI:  https://doi.org/10.1016/j.celrep.2025.116414
  2. Nat Struct Mol Biol. 2025 Oct 06.
    Reporter CRISPR screens decipher cis-regulatory and trans-regulatory principles at the Xist locus.
    Till Schwämmle, Gemma Noviello, Eleni Kanata, Jonathan J Froehlich, Melissa Bothe, Alexandra Martitz, Aybuge Altay, Jade Scouarnec, Vivi-Yun Feng, Heleen Mallie, Martin Vingron, Edda G Schulz.
      Developmental genes are controlled by an ensemble of cis-acting regulatory elements (REs), which in turn respond to multiple trans-acting transcription factors (TFs). Understanding how a cis-regulatory landscape integrates information from many dynamically expressed TFs has remained a challenge. Here we develop a combined CRISPR screening approach using endogenous RNA and RE reporters as readouts. Applied to the murine Xist locus, which is crucial for X-chromosome inactivation in females, this method allows us to comprehensively identify Xist-controlling TFs and map their TF-RE wiring. We find a group of transiently upregulated TFs, including ZIC3, that regulate proximal REs, driving the binary activation of Xist expression. These basal activators are more highly expressed in cells with two X chromosomes, potentially governing female-specific Xist upregulation. A second set of developmental TFs that include OTX2 is upregulated later during differentiation and targets distal REs. This regulatory axis is crucial to achieve high levels of Xist RNA, which is necessary for X-chromosome inactivation. OCT4 emerges as the strongest activator overall, regulating both proximal and distal elements. Our findings support a model for developmental gene regulation, in which factors targeting proximal REs drive binary on-off decisions, whereas factors interacting with distal REs control the transcription output.
    DOI:  https://doi.org/10.1038/s41594-025-01686-3
  3. Nat Commun. 2025 Oct 09. 16(1): 8984
    IceQream: Quantitative chromosome accessibility analysis using physical TF models.
    Akhiad Bercovich, Aviezer Lifshitz, Michal Eldar, Saifeng Cheng, Roni Stok Ranen, Yonatan Stelzer, Amos Tanay.
      Single-cell mapping of chromosomal accessibility patterns has recently led to improved predictive modelling of epigenomic activity from sequence. However, quantitative models explaining the epigenome using directly interpretable components are still lacking. Here we develop IceQream (IQ), a modelling strategy and inference algorithm for regressing accessibility from sequences using physical models of transcription factor (TF) binding. IQ uses spatial integration of sequences over a range of TF-DNA affinities and localization relative to the target locus. It infers TF effective concentrations as latent variables that activate or repress regulatory elements in a non-linear fashion. These are supplemented with synergistic and antagonistic pairwise interactions between TFs. Analysis of both human and mouse data shows that IQ derives similar, and in some cases, better performance compared to state-of-the-art deep neural network models. IQ provides an essential mechanistic and explicable baseline for further developments toward understanding gene and genome regulation from sequence.
    DOI:  https://doi.org/10.1038/s41467-025-63925-x
  4. Nat Commun. 2025 Oct 08. 16(1): 8955
    Fosl2 facilitates chromatin accessibility to determine developmental events during follicular maturation.
    Hongyong Zhang, Zechen Li, Yanmei Zhu, Wencong Lyu, Wenlu Wei, Haochen Wang, Shuangjie Tian, Wei Yue, Jiajing Zhong, Qing-Yuan Sun, Yiting Guan.
      Granulosa cells (GCs) are the most dynamically responsive cell lineage to encourage continuous folliculogenesis; however, developmental dynamics and interplay with downstream transcription circuitry remain unclear. Here, we unravel the redistribution of genome-wide chromatin areas that drive broad developmental-related transcriptomic alterations during follicular maturation in murine and porcine GCs. Distinct GC-activated accessibility regions (GAAs) at the ovulatory phase are responsible for augmenting flanking GC-involved developmental gene (GDG) expression, which are essential for transcriptional responses to developmental cues. Mechanistically, the transcription factor Fosl2 is strongly recruited to GAAs, facilitating chromatin accessibility state transition. Elevated GAA signals driven by Fosl2 loading induce a significant upregulation of adjacent GDG expression. Additionally, GC-specific Fosl2 deletion in mice perturbs GC cellularity, leading to subfertility related to reproductive aging. Together, we highlight a dynamic chromatin accessibility landscape during follicular maturation, revealing the indispensable Fosl2 function not only controls transcriptional activation via a reconfigured chromatin state, but also orchestrates intricate signaling pathways that are fundamental for ovulation and reproduction.
    DOI:  https://doi.org/10.1038/s41467-025-64009-6
  5. Nat Commun. 2025 Oct 10. 16(1): 9024
    HAND2 invades nucleolar condensates to pioneer lineage-specific cardiac pacemaker gene programs.
    Kartik Kulkarni, Gabriella Quinn, Jared Dela Rosa, Sean Goetsch, Vrushali Pandit, Lin Wang, Akane Sakaguchi, Sushama Sivakumar, Nikhil V Munshi.
      Although best known as the site for ribosome assembly, the nucleolus organizes heterochromatin into transcriptionally repressed Nucleolus-Associated Domains (NADs). NADs harbor many genes involved in cell-type specification, yet the mechanisms by which transcription factors (TFs) access this heterochromatin to activate gene expression remain unknown. Using a model of TF-induced cardiac pacemaker reprogramming, we conclusively establish that nucleolar localization of HAND2 is required for successful lineage conversion. Moreover, we perform unbiased transcriptional profiling to demonstrate that pacemaker gene programs are highly compartmentalized within the nucleus. Finally, we show that HAND2 homodimers invade nucleolar condensates and concentrate within the nucleolus to bind palindromic motifs required for activating lineage-specific enhancers buried within NADs. Taken together, our data highlight a key role for the nucleolus in orchestrating pacemaker gene expression by HAND2. More broadly, these results suggest that TF localization to sub-nuclear heterochromatin domains may represent a potent strategy for activating lineage-specific gene programs.
    DOI:  https://doi.org/10.1038/s41467-025-64076-9
  6. Genome Biol. 2025 Oct 06. 26(1): 340
    Cisformer: a scalable cross-modality generation framework for decoding transcriptional regulation at single-cell resolution.
    Luzhang Ji, Qihang Zou, Ke Tang, Chenfei Wang.
      Single-cell multiomic technologies enable the joint analysis of different modalities, but face challenges due to experimental complexity. Current computational methods for single-cell cross-modality translation lack biological interpretability. Here, we present Cisformer, a cross-attention-based generative model tailored for cross-modality generation between gene expression and chromatin accessibility at single-cell resolution. Systematic benchmarking demonstrates the superior accuracy and generalization of Cisformer against existing methods. Cisformer leverages its inherent interpretability to precisely link cis-regulatory elements to target genes, facilitating the identification of functional transcription factors associated with tumorigenesis and aging. Overall, Cisformer is a powerful tool for single-cell multiomic data analysis.
    Keywords:   Cis-regulatory element; Cross-modality generation; Model interpretability; Single-cell multiomics; Transcription factor; Transcriptional regulation; Transformer
    DOI:  https://doi.org/10.1186/s13059-025-03823-z
  7. Nucleic Acids Res. 2025 Sep 23. pii: gkaf940. [Epub ahead of print]53(18):
    Ultra-fast variant effect prediction using biophysical transcription factor binding models.
    Rezwan Hosseini, Ali Tugrul Balci, Dennis Kostka, Nathan Clark, Maria Chikina.
      Sequence variation within transcription factor (TF)-binding sites can significantly affect TF-DNA interactions, influencing gene expression and contributing to disease susceptibility or phenotypic traits. Despite recent progress in deep sequence-to-function models that predict functional output from sequence data, these methods perform inadequately on some variant effect prediction tasks, especially with common genetic variants. This limitation underscores the importance of leveraging biophysical models of TF binding to enhance interpretability of variant effect scores and facilitate mechanistic insights. We introduce motifDiff, a novel computational tool designed to quantify variant effects using mono- and dinucleotide position weight matrices. motifDiff offers several key advantages, including scalability to score millions of variants within minutes, implementation of statistically rigorous normalization strategy critical for optimal performance, and support for both dinucleotide and mononucleotide models. We demonstrate motifDiff's efficacy by evaluating it across diverse ground truth datasets that quantify the effects of common variants in vivo, thereby establishing robust benchmarks for the predictive value of variant effect calculations. Finally, we show that our tool provides unique insights when interpreting human accelerated regions. motifDiff is available as a standalone Python application at https://github.com/rezwanhosseini/MotifDiff.
    DOI:  https://doi.org/10.1093/nar/gkaf940
  8. Genome Res. 2025 Oct 06. pii: gr.280633.125. [Epub ahead of print]
    Integrative chromatin state annotation of 234 human ENCODE4 cell types using Segway.
    Marjan Farahbod, Aboud Diab, Paul Sud, Meenakshi S Kagda, Ian Whaling, Mehdi Foroozandeh, Ishan Goel, Habib Daneshpajouh, Benjamin Hitz, J Michael Cherry, Maxwell W Libbrecht.
      The fourth and final phase of the ENCODE consortium has newly profiled epigenetic activity in hundreds of human tissues. Chromatin state annotations created by segmentation and genome annotation (SAGA) methods such as Segway have emerged as the predominant integrative summary of such data sets. Here, we present the ENCODE4 Catalog of Segway Annotations, a set of sample-specific genome-wide chromatin state annotations of 234 human biosamples inferred from 1,794 genomics experiments. This catalog identifies genomic elements, accurately captures cell type-specific regulatory patterns, and facilitates discovery of elements involved in phenotype and disease.
    DOI:  https://doi.org/10.1101/gr.280633.125
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒22 at 17:35.