bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–12–07
ten papers selected by
Connor Rogerson, University of Cambridge
  1. Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation.
  2. Two CTCF motifs impede cohesin-mediated DNA loop extrusion.
  3. MYC drives left-handed Z-DNA formation to shape gene expression.
  4. Distinct transcription factor interactions drive HOXB13 activity in different stages of prostate cancer.
  5. An archaeal transcription factor bridges prokaryotic and eukaryotic regulatory paradigms.
  6. Mapping single-cell diploid chromatin fiber architectures using DAF-seq.
  7. JASPAR 2026: expansion of transcription factor binding profiles and integration of deep learning models.
  8. Multiscale structure of chromatin condensates explains phase separation and material properties.
  9. A split luciferase biosensing platform for detection and imaging of chromatin loops in individual live cells.
  10. PLETHORA transcription factors orchestrate epigenetic silencing of bivalent chromatin to promote root meristem development in rice.
  1. Nat Cell Biol. 2025 Dec 02.
    Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation.
    Yeqiao Zhou, Atishay Jay, Noah Burget, Tobias Friedrich, Sora Yoon, Jessica Alsing, Guy Nir, Rudolf Grosschedl, Golnaz Vahedi, Robert B Faryabi.
      Multiple enhancers, often separated by vast genomic distances, regulate key genes. However, how the folding of individual chromatin fibres enables cell-type-restricted multi-enhancer regulation remains unclear. Here, using acute protein degradation and time-resolved chromatin conformation capture in mantle cell lymphoma, we found that the B cell-lineage-determining factor EBF1 organizes multiple enhancers around sparsely distributed genes essential for B cell identity and oncogenesis. Time-resolved sub-diffraction optical tracing of more than 100,000 chromatin fibres further revealed diverse topological conformations that facilitate multi-enhancer interactions. Mechanistically, we discovered that enhancer positioning at local topological centres is required for promoter engagement, with EBF1 acting as a permeable barrier to loop-extruding cohesin at enhancers. Extending these findings to T cell leukaemia, we show that lineage-determining transcription factors such as EBF1 and TCF1 radially position enhancers within gene loci to enable multi-enhancer regulation of key oncogenes at the single-allele level.
    DOI:  https://doi.org/10.1038/s41556-025-01827-2
  2. Mol Cell. 2025 Dec 04. pii: S1097-2765(25)00897-4. [Epub ahead of print]85(23): 4304-4317.e9
    Two CTCF motifs impede cohesin-mediated DNA loop extrusion.
    Roman Barth, Richard Janissen, Laura Muras, Jaco van der Torre, Gabriele Litos, Eli van der Sluis, Ashmiani van den Berg, Iain F Davidson, Jan-Michael Peters, Cees Dekker.
      Human cohesin extrudes DNA into loops and is positioned along the genome by stalling at the human CCCTC-binding factor (CTCF) upon encountering its N-terminal region (NTR). The mechanism underlying this stalling, however, is unresolved. Using single-molecule assays that monitor DNA loop extrusion (LE) in the presence of NTR fragments, we identify two amino acid motifs, YDF and KTYQR, which hinder LE. KTYQR is found to completely block LE activity, while YDF hinders cohesin from completing LE step cycles and converts cohesin into a unidirectional extruder by strengthening the affinity of STAG1 to DNA. We thus identify two distinct NTR motifs that stall LE via different yet synergistic mechanisms, highlighting the multifaceted ways employed by CTCF to modulate LE to shape and regulate genomes.
    Keywords:  AlphaFold; CTCF; DNA loop extrusion; chromosome organization; cohesin; magnetic tweezers; single-molecule fluorescence
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.001
  3. Nat Commun. 2025 Dec 01.
    MYC drives left-handed Z-DNA formation to shape gene expression.
    Xinyi Wan, Haonan Fan, Zhuoning Li, Yixuan Du, Yu Liu, Weiwu Zeng, Zhongxing Sun, Juejia Shao, Junqi Jia, Yanjun Zhang, Dong Fang.
      DNA topology is critical for regulating transcription and maintaining cellular homeostasis. Z-DNA is a left-handed DNA helix in regions with high transcriptional activity. Its physiological function remains poorly understood. Here, we demonstrate that oncoprotein MYC induces the formation of Z-DNA by recruiting the chromatin remodeler FACT, independent of RNA Polymerase II activity. FACT facilitates Z-DNA formation by remodeling H2A/H2B dimers within intact nucleosomes. Additionally, the phosphorylation of FACT regulates its liquid-liquid phase separation, promoting its efficient recruitment to chromatin by MYC. Through a genome-wide analysis and characterization of engineered Z-DNA promoters, we found that Z-DNA directly facilitates the loading of RNA Polymerase II, thereby promoting transcriptional activity. This study elucidates the molecular mechanisms of Z-DNA dynamics and emphasizes its functional importance in transcriptional regulation, providing insights into the role of left-handed DNA structures in chromatin biology and MYC-driven cancer.
    DOI:  https://doi.org/10.1038/s41467-025-66886-3
  4. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2500327122
    Distinct transcription factor interactions drive HOXB13 activity in different stages of prostate cancer.
    Betul Ersoy-Fazlioglu, Shreyas Lingadahalli, Umut Berkay Altintas, Ahmet Cingoz, Emirhan Tekoglu, Ivan Pak Lok Yu, Meric Dikbas, Olka Missaghimamaghani, Kerim Yavuz, Hans Adomat, Ibrahim Kulac, Tunc Morova, Kevin Xiao, Martin Gleave, Ladan Fazli, Paloma Cejas, Artem Cherkasov, Wilbert Zwart, Michael Christoph Haffner, Henry W Long, Colin Collins, Tugba Bagci-Onder, Nathan A Lack.
      HOXB13 is a lineage-specific transcription factor that plays a critical role in initiation and progression of prostate cancer (PCa). While most research has focused on the role of HOXB13 on androgen receptor (AR) activity, here we demonstrate that HOXB13 is frequently expressed in AR-negative tumors and is essential for the proliferation of both AR-positive and -negative PCa models. Strikingly, HOXB13 is remarkably selective and has almost no effect on nonprostatic tissues. Despite this common essentiality in PCa, HOXB13 activity is markedly different in AR-negative stem cell-like tumors, where interactions with the AP-1 change the HOXB13 cistrome and interactome. Yet despite these distinct activities, HOXB13 activity is commonly mediated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction alters chromatin accessibility at HOXB13-binding sites, causing increased proliferation in AR-negative PCa. Overall, this work demonstrates a distinct mechanism of action for HOXB13 and highlights its critical role in AR-negative castration-resistant PCa.
    Keywords:  HOXB13; androgen receptor; mSWI/SNF; prostate cancer
    DOI:  https://doi.org/10.1073/pnas.2500327122
  5. Cell. 2025 Dec 01. pii: S0092-8674(25)01241-3. [Epub ahead of print]
    An archaeal transcription factor bridges prokaryotic and eukaryotic regulatory paradigms.
    Fernando Medina Ferrer, Dipti D Nayak.
      Archaeal transcription is a hybrid of eukaryotic and prokaryotic features: an RNA polymerase II (RNAPII)-like polymerase transcribes genes organized in circular chromosomes within cells devoid of a nucleus. Consequently, archaeal genomes are depleted of transcriptional regulators found in other domains of life. Here, we outline the discovery of a cryptic, archaea-specific family of ligand-binding regulatory transcription factors (TFs), called AmzR (archaeal metabolite-sensing zipper-like regulators). We identify AmzR using an evolution-based genetic screen and show that it is a repressor of methanogenic growth on methylamines in the archaeon Methanosarcina acetivorans. AmzR binds its target promoters as an oligomer using paired basic α-helices akin to eukaryotic leucine zippers. AmzR also binds methylamines, which reduces its DNA-binding affinity and allows it to function as a one-component system commonly found in prokaryotes, while containing a eukaryotic-like DNA-binding motif. The AmzR family of TFs are widespread in archaea and broaden the scope of innovations at the prokaryote-eukaryote interface.
    Keywords:  archaea; bHLH; bZIP; methanogen; methanogenesis; methylamines; one-component system; repressor; transcription factor; transcriptional regulator
    DOI:  https://doi.org/10.1016/j.cell.2025.10.036
  6. Nat Biotechnol. 2025 Dec 03.
    Mapping single-cell diploid chromatin fiber architectures using DAF-seq.
    Elliott G Swanson, Yizi Mao, Benjamin J Mallory, Mitchell R Vollger, Stephanie C Bohaczuk, Christopher B Oliveira, Daniel B Lyon, Jane Ranchalis, Nancy L Parmalee, Barak A Cohen, James T Bennett, Andrew B Stergachis.
      Gene regulation is orchestrated by the co-binding of proteins along chromosome-length chromatin fibers within single cells, yet the heterogeneity of this occupancy between haplotypes and cells remains poorly resolved in diploid organisms. Here we present Deaminase-Assisted single-molecule chromatin Fiber sequencing (DAF-seq), which enables single-molecule footprinting at near-nucleotide resolution while synchronously profiling single-molecule chromatin states and DNA sequence. DAF-seq illuminates cooperative protein occupancy at individual regulatory elements and resolves the functional impact of somatic variants and rare chromatin epialleles. Single-cell DAF-seq (scDAF-seq) generates chromosome-length protein co-occupancy maps across 99% of each individual cell's mappable genome. scDAF-seq uncovers extensive chromatin plasticity both within and between single diploid cells, with chromatin actuation diverging by 61% between haplotypes within a cell, and 63% between cells. Moreover, we find that regulatory elements are preferentially co-actuated along the same fiber in a distance-dependent manner that mirrors cohesin-mediated loops. Overall, DAF-seq enables the characterization of protein occupancy across entire chromosomes with single-nucleotide, single-molecule, single-haplotype and single-cell precision.
    DOI:  https://doi.org/10.1038/s41587-025-02914-3
  7. Nucleic Acids Res. 2025 Dec 02. pii: gkaf1209. [Epub ahead of print]
    JASPAR 2026: expansion of transcription factor binding profiles and integration of deep learning models.
    Damla Ovek Baydar, Ieva Rauluseviciute, Dina R Aronsen, Romain Blanc-Mathieu, Ine Bonthuis, Herman de Beukelaer, Katalin Ferenc, Alice Jegou, Vipin Kumar, Roza Berhanu Lemma, Jérémy Lucas, Mathis Pochon, Chang M Yun, Vivekanandan Ramalingam, Salil Sanjay Deshpande, Aman Patel, Georgi K Marinov, Austin T Wang, Alejandro Aguirre, Jaime A Castro-Mondragon, Damir Baranasic, Jeanne Chèneby, Sveinung Gundersen, Morten Johansen, Aziz Khan, Marieke L Kuijjer, Eivind Hovig, Boris Lenhard, Albin Sandelin, Klaas Vandepoele, Wyeth W Wasserman, François Parcy, Anshul Kundaje, Anthony Mathelier.
      JASPAR (https://jaspar.elixir.no/) is an open-access database that has provided high-quality, manually curated, and non-redundant DNA binding profiles for transcription factors (TFs) as position frequency matrices (PFMs) for over 20 years. We expanded the CORE (306 new profiles, 12% increase) and UNVALIDATED (433, 60% increase) collections with new PFMs and updated 13 existing profiles. We updated the TF binding site predictions and genome tracks for eight species. TF binding profile clusters and familial TF binding sites were updated accordingly. We integrate the inMOTIFin software to easily simulate regulatory sequences using JASPAR PFMs. To enrich TFs' annotations, we provide scientific literature-based human TF target information. Notably, this release features a deep learning (DL) collection, providing a paradigm shift in modeling and characterizing TF-DNA interactions with 1259 BPNet models trained on Homo sapiens ENCODE chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets from 240 TFs and interpreted to reveal predictive motif patterns for the models. The motifs associated with the same TF were clustered to provide a summary of the binding properties, resulting in 240 primary and 113 alternative motif patterns in the DL collection. The JASPAR 2026 collections lay a foundation for future endeavors in genomic research, serving the scientific community in uncovering the mechanisms of gene regulation.
    DOI:  https://doi.org/10.1093/nar/gkaf1209
  8. Science. 2025 Dec 04. 390(6777): eadv6588
    Multiscale structure of chromatin condensates explains phase separation and material properties.
    Huabin Zhou, Jan Huertas, M Julia Maristany, Kieran Russell, June Ho Hwang, Run-Wen Yao, Nirnay Samanta, Joshua Hutchings, Ramya Billur, Momoko Shiozaki, Xiaowei Zhao, Lynda K Doolittle, Bryan A Gibson, Andrea Soranno, Margot Riggi, Jorge R Espinosa, Zhiheng Yu, Elizabeth Villa, Rosana Collepardo-Guevara, Michael K Rosen.
      The structure and interaction networks of molecules within biomolecular condensates are poorly understood. Using cryo-electron tomography and molecular dynamics simulations, we elucidated the structure of phase-separated chromatin condensates across scales, from individual amino acids to network architecture. We found that internucleosomal DNA linker length controls nucleosome arrangement and histone tail interactions, shaping the structure of individual chromatin molecules within and outside condensates. This structural modulation determines the balance between intra- and intermolecular interactions, which governs the molecular network, thermodynamic stability, and material properties of chromatin condensates. Mammalian nuclei contain dense clusters of nucleosomes whose nonrandom organization is mirrored by the reconstituted condensates. Our work explains how the structure of individual chromatin molecules determines physical properties of chromatin condensates and cellular chromatin organization.
    DOI:  https://doi.org/10.1126/science.adv6588
  9. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1324. [Epub ahead of print]53(22):
    A split luciferase biosensing platform for detection and imaging of chromatin loops in individual live cells.
    Nicholas G Heath, J Antonio Gomez, Sean P McGinty, Henriette O'Geen, David J Segal.
      Eukaryotic cells regulate higher-order chromatin architecture, gene expression, and gene recombination via compaction of the genome into chromatin loops and topologically associating domains (TADs). While chromatin architecture has been thoroughly characterized for many eukaryotic genomes using cell-destructive techniques such as 3C-based methods, live-cell biosensing tools that can probe three-dimensional chromatin contacts in real-time are lacking. Using a dual dCas9 DNA biosensor based on a split NanoLuc luciferase reporter, we directly detected chromatin loops in live cells using luminescence quantification in a luminometer. We observed signal-to-background ratios of up to 10-fold. In addition, we directly visualized chromatin looping at the MYC TAD in live cells using high-resolution, low-light live-cell imaging. Our biosensing platform therefore provides a useful methodology for live-cell, real-time detection of known or novel loops and for monitoring looping dynamics upon alterations in cell state.
    DOI:  https://doi.org/10.1093/nar/gkaf1324
  10. Mol Plant. 2025 Dec 02. pii: S1674-2052(25)00426-5. [Epub ahead of print]
    PLETHORA transcription factors orchestrate epigenetic silencing of bivalent chromatin to promote root meristem development in rice.
    Qi Li, Junjie Li, Xintian Tang, Chen Chu, Jing Wang, Dao-Xiu Zhou, Yu Zhao.
      The maintenance of stem cells within root meristem is the foundation for continuous growth of the root system. The PLETHORA (PLT) transcription factors have a function to control patterning of the root meristem, but the underlying molecular mechanism remains unclear. In this work we show that rice PLT3, PLT4 and PLT5 have a function to promote a repressive chromatin state to maintain stem cell fate in the root meristem. We show that PLT5 interacts with Polycomb Repressive Complex 2 (PRC2) that deposits the repressive mark H3K27me3 and the histone demethylase JMJ703 that removes the active mark H3K4me3 in rice root meristem cells. In addition, JMJ703 itself associates with PRC2 proteins. Loss of PLT3, PLT4 and PLT5 function resulted in decreased PRC2-association and H3K27me3, increased H3K4me3, and upregulated expression of genes decorated with the two marks in the root meristem. Further analysis indicates that the PLT interactions with PRC2 and JMJ703 enhance the H3K27me3/H3K4me3 ratio at a set of bivalent genes to maintain their silent state. These results uncover a chromatin mechanism by which PLTs control the stem cell fate in the rice root meristem.
    Keywords:  Bivalent; Cell fate; JMJ703; PLETHORA; Polycomb-repressive complex2 (PRC2)
    DOI:  https://doi.org/10.1016/j.molp.2025.11.012
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