bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2026–01–04
six papers selected by
Connor Rogerson, University of Cambridge
  1. BRD2 bridges TFIID and MOF-H4K16ac-containing nucleosomes to promote transcriptional initiation.
  2. Site-specific phosphorylation of LRP regulates FLC chromatin looping and flowering.
  3. Quantifying transcription factor specificity with advanced DNA universal microarrays featuring long and modified binding sites.
  4. A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform.
  5. A mitotic bookmark coordinates transcription and replication in Drosophila embryos.
  6. The BRD4-nucleosome interaction is enhanced modestly and non-selectively by histone acetylation.
  1. Mol Cell. 2025 Dec 31. pii: S1097-2765(25)00984-0. [Epub ahead of print]
    BRD2 bridges TFIID and MOF-H4K16ac-containing nucleosomes to promote transcriptional initiation.
    Bin Zheng, Ruxuan Qiu, Sarah Gold, Marta Iwanaszko, Yuki Aoi, Benjamin Charles Howard, Madhurima Das, Ali Shilatifard.
      Members of the bromodomain and extraterminal domain (BET) protein family play a central role in transcription by RNA polymerase II (RNA Pol II). Small-molecule inhibitors that block interaction between BET bromodomains and acetylated histones have been developed for disease therapeutics. However, the BET protein BRD4 does not require bromodomains to perform its major transcriptional elongation control, and mechanisms by which other BET proteins regulate RNA Pol II remain insufficiently understood. Addressing the disparity between pan-BET degraders and BRD4-specific depletion, we report that the BET protein BRD2 generally functions to promote transcriptional initiation in a bromodomain-dependent manner at both promoters and enhancers in human cell lines. We demonstrate that BRD2 bromodomains preferentially bind to histone H4 harboring MOF-mediated H4K16ac, while the BRD2 C-terminal domain facilitates recruitment of TFIID. Our studies provide mechanistic insight into distinct roles for BRD2 and BRD4 in transcriptional initiation and elongation control for proper regulation of gene expression.
    Keywords:  BET inhibitors; BRD2; BRD4; H4K16ac; JQ1; MOF; RNA polymerase II; TFIID; chromatin; dBET6; gene expression; transcription; transcription initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.010
  2. Sci Adv. 2026 Jan 02. 12(1): eadz0645
    Site-specific phosphorylation of LRP regulates FLC chromatin looping and flowering.
    Sheng Fan, Yu Zhang, Shaobo Zhu, Zhenfeng Teng, Qiqi Zhang, Yuanyuan Yan, Lisha Shen.
      Emerging evidence suggests that multiple RNA recognition motif (RRM)-containing proteins are involved in transcriptional regulation, yet the underlying mechanisms remain largely unclear. Here, we show that the previously uncharacterized LATE-FLOWERING RRM-CONTAINING PROTEIN (LRP) prevents 5'-3' chromatin looping of the key floral repressor gene FLOWERING LOCUS C (FLC) via direct association with its 5' and 3' genomic regions. Loss of LRP function leads to increased 5'-3' gene looping, reduced RNA polymerase II (Pol II) occupancy at the FLC locus, thereby increasing FLC transcription and delaying flowering in Arabidopsis thaliana. Furthermore, site-specific phosphorylation of LRP at serine 17, mediated by the kinase PRP4KA, is essential for LRP protein stability and its function in preventing FLC chromatin looping and Pol II recruitment. Our findings reveal that site-specific phosphorylation of LRP by PRP4KA precludes FLC gene loop formation, constituting a key mechanism for FLC transcriptional repression to ensure timely flowering.
    DOI:  https://doi.org/10.1126/sciadv.adz0645
  3. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1382. [Epub ahead of print]53(22):
    Quantifying transcription factor specificity with advanced DNA universal microarrays featuring long and modified binding sites.
    Yuval Bayer, Michael P O'Hagan, Irina Miodownik, Ariel Afek.
      Transcription factor (TF)-DNA binding specificity, shaped by both sequence and epigenetic modifications, is central to gene regulation. Universal protein-binding microarrays (uPBMs), based on compact de Bruijn sequence designs, have emerged as powerful tools to characterize the specificity of hundreds of TFs. However, conventional uPBMs binding measurements are limited to direct measurement of short ($\le$8 bp) motifs composed of four canonical bases, lacking the ability to resolve the effects of extended sequence context or modifications. To address these limitations, we developed two enhanced platforms: Ex-uPBM, based on extended higher-order de Bruijn sequences, and Mod-uPBM, based on de Bruijn sequences that incorporate modified bases. Applying Ex-uPBM to known TFs allowed direct measurements for motifs up to 10 bp long and exposed specificity to flanking regions, unattainable in standard uPBM. By applying Mod-uPBM, we measured the effect of 5-methylcytosine (5mC) in all possible contexts, summarized in a full energetic position weight matrix (PWM). This PWM not only reproduced known TF binding specificity but also revealed context-specific energetic effects of 5mC in the full consensus motif at single-nucleotide resolution. Together, our platforms provide a robust and scalable strategy for TF binding quantification that better captures the sequence and modification complexity of genomic DNA.
    DOI:  https://doi.org/10.1093/nar/gkaf1382
  4. Science. 2026 Jan 01. eaeb3627
    A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform.
    Siddhant U Jain, Kaylyn E Williamson, Alexander W Ying, Aasha M Turner, Ruidong Jerry Jiang, Shaunak Raval, Kevin So, Maxwell J Allison, Akshay Sankar, Daniel D Sáme Guerra, Yutong Lin, Zhe Jiang, Nazar Mashtalir, Henry W Rohrs, Cheryl F Lichti, Tom W Muir, Malvina Papanastasiou, Joao A Paulo, Steven P Gygi, Michael L Gross, Cigall Kadoch.
      Mammalian SWI/SNF chromatin remodeling complexes modulate DNA accessibility and gene expression; however, their genomic targeting mechanisms remain incompletely understood. Here, we identify SWIFT (SWI/SNF Ig-fold for transcription factor interactions), a conserved transcription factor (TF) binding platform on the SMARCD subunits. SWIFT is necessary and sufficient for direct engagement with the transactivation domain of PU.1. A single amino acid mutation disrupts PU.1-mSWI/SNF binding, impairs complex targeting, and attenuates oncogenic transcription and proliferation in PU.1-dependent cancer cells. Dominant expression of the SWIFT domain in isolation sequesters TFs from mSWI/SNF and poisons TF-addicted cancer cells. Finally, TFs across diverse families interact with SMARCD paralog-specific SWIFT domains. These results define a major mechanism of cell type- and disease-specific mSWI/SNF chromatin targeting and inform approaches toward therapeutic modulation.
    DOI:  https://doi.org/10.1126/science.aeb3627
  5. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1429. [Epub ahead of print]53(22):
    A mitotic bookmark coordinates transcription and replication in Drosophila embryos.
    Chun-Yi Cho, Patrick H O'Farrell.
      Collisions between advancing replication forks and elongating transcripts pose a universal threat. During the rapid nuclear division cycles in early Drosophila embryos, coordinating transcription and replication is critical to reduce the risk of collisions. In each cycle, replication begins immediately after mitosis, while transcription starts 3 min later, overlapping replication for the remainder of interphase. We previously showed that transcription depends on Brd4, which forms hubs at active genes. Here, we show that Brd4 persists on mitotic chromosomes as bookmarks of transcriptional activation. Upon anaphase entry, the replication initiation factor Cdc7 forms Brd4-dependent foci that promote early replication in the following interphase. Additionally, Cdc7 activity disperses Brd4 such that post-mitotic transcription occurs only after a new round of Brd4 hub assembly. Early initiation of replication in conjunction with deferred transcription is proposed to allow unimpeded transcriptional elongation behind advancing replication forks. Supporting this, inhibiting Cdc7 delayed replication, stabilized Brd4 bookmarks, and resulted in premature transcription with elongation defects. We propose that Cdc7 triggers a functional switch in Brd4 that enforces temporal ordering of the initiation of replication and transcription, thereby minimizing collisions. This switching process might underlie the widespread correlation between transcriptional activity and early replication.
    DOI:  https://doi.org/10.1093/nar/gkaf1429
  6. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1406. [Epub ahead of print]53(22):
    The BRD4-nucleosome interaction is enhanced modestly and non-selectively by histone acetylation.
    Lucien S Lambrechts, Xavier J Reid, Lucas Kambanis, Clement Luong, Erekle Kobakhidze, Andrea Daners, Yichen Zhong, Karishma Patel, Charlotte K Franck, Hakimeh Moghaddas Sani, Cameron Taylor, Jason K K Low, Richard J Payne, Joel P Mackay.
      BRD4 regulates gene transcription in complex eukaryotes, in part through the binding of its tandem bromodomains to acetylated lysine residues found in histones and transcription factors. Despite pharmacological inhibition of these domains showing promise in preclinical studies, clinical trial data have been less encouraging so far. A stronger understanding of BRD4 biochemistry could provide a route to better outcomes. To advance on prior work, which has focused almost entirely on the binding of isolated bromodomains and acetylated peptides, we have sought the preferred nucleosomal binding partner of full-length BRD4. We demonstrate that BRD4 binds with sub-micromolar affinity to both unmodified nucleosomes and to DNA alone. In strong contrast to BRD4-peptide interactions, we also find that the affinity of BRD4 for nucleosomes is increased only 2-4-fold by histone acetylation and that this affinity has little dependence on the acetylation pattern. Despite this modest effect of acetylation, binding of BRD4 to acetyllysine in the nucleosome was more resistant to perturbation by mutation or small-molecule inhibition than BRD4-peptide interactions. Our work on a more complete in vitro system helps bridge the gap between cellular and prior in vitro work and provides clues to explain the in vivo chromatin occupancy profile of BRD4 and how it changes upon therapeutic inhibition.
    DOI:  https://doi.org/10.1093/nar/gkaf1406
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