bims-crepig 2025-09-28 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2025–09–28
seven papers selected by
Connor Rogerson, University of Cambridge

Emergence of activation or repression in transcriptional control under a fixed molecular context.
Control of myeloid lineage fidelity and response to stimuli by ISWI-enforced nucleosome phasing.
KMT2D temporally activates neuronal transcriptional factor genes to mediate cerebellar granule cell differentiation.
Mammalian H4K16ac regulates the spatiotemporal order of genome replication rather than gene expression.
TOC1 phosphorylation disproportionally enhances chromatin binding at rhythmic gene promoters.
Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance.
Coordinated control of genome-nuclear lamina interactions by topoisomerase 2B and lamin B receptor.

Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2413715122

Emergence of activation or repression in transcriptional control under a fixed molecular context.

Rosa Martinez-Corral, Dhana Friedrich, Robert Frömel, Lars Velten, Jeremy Gunawardena, Angela H DePace.

  Transcription factors (TFs) can be both activators and repressors of gene transcription. This can manifest as "duality," where the transcriptional response increases (activation) with TF concentration in one context but decreases (repression) in another context, or as "nonmonotonicity," where, in the same context, the response increases in part of the concentration range and decreases outside that range. Here we use biophysical models of gene regulation to investigate how duality and nonmonotonicity relate to the interactions between a TF, Polymerase and the regulatory DNA. We distinguish two modes of TF action on Polymerase: "coherent," with interactions either positive or negative, and "incoherent," where interactions are a mix of both. For TFs that act incoherently from a single TF-DNA binding site, nonmonotonicity can arise, but only under nonequilibrium models. For single-site models, we show that nonmonotonicity can never happen under the common thermodynamic models of gene regulation, which consider equilibrium conditions and ignore the dissipative nature of the transcription process. Moreover, we show that merely changing the TF-DNA binding affinity, while keeping other features fixed, can tune the response between activation and repression, with responses either evaluated as a function of TF concentration or site number. Using the mammalian Sp1 as a case study and synthetically designed target sequences, we find experimental evidence for nonmonotonicity, and activation or repression tuned by affinity, which we interpret as evidence of incoherent action. Our work highlights the importance of moving from a TF-centric view to a systems view when reasoning about transcriptional control.

Keywords:  duality; gene regulation; nonequilibrium regulation; nonmonotonicity; transcription factor

DOI:  https://doi.org/10.1073/pnas.2413715122
Immunity. 2025 Sep 25. pii: S1074-7613(25)00413-3. [Epub ahead of print]

Control of myeloid lineage fidelity and response to stimuli by ISWI-enforced nucleosome phasing.

Sara Polletti, Júlia Melià-Alomà, Francesco Pileri, Chiara Anna Di Lena, Viviana Piccolo, Alessandro Cuomo, Tomas Stopka, Francesco Gualdrini, Gioacchino Natoli.

  The interplay between chromatin remodelers and pioneer transcription factors (TFs) regulates cis-regulatory element accessibility to maintain cell identity and transcriptional fidelity. We investigated the impact of imitation of switch (ISWI) chromatin remodelers, key regulators of nucleosome spacing, on macrophage differentiation and activation, focusing on SMARCA5, the sole ISWI ATPase in myeloid cells. Conditional Smarca5 deletion in bone marrow-derived macrophages disrupted nucleosome phasing near sites bound by PU.1, a pioneer TF essential for myeloid identity, without altering PU.1 occupancy. However, SMARCA5 loss increased accessibility at motifs bound by C/EBPβ, a weak pioneer TF, enabling binding to regulatory regions active in non-hematopoietic lineages and causing lineage-inappropriate transcription. These changes also increased accessibility at sites bound by stimulus-induced TFs, leading to macrophage hyperactivation and mis-expression of stimulus-inappropriate genes. Thus, SMARCA5-dependent nucleosome phasing restrains C/EBPβ and stimulus-induced TF binding, ensuring transcriptional fidelity during macrophage lineage specification and activation, with likely similar roles in other immune cell types.

Keywords:  ISWI chromatin remodelers; PU.1; Smarca5; chromatin remodeling; immune cell regulation; macrophages; nucleosome phasing; pioneer transcription factors; transcriptional fidelity

DOI:  https://doi.org/10.1016/j.immuni.2025.09.002
Sci Adv. 2025 Sep 26. 11(39): eadu7174

KMT2D temporally activates neuronal transcriptional factor genes to mediate cerebellar granule cell differentiation.

Shilpa S Dhar, Kyung-Pil Ko, Jinho Jang, Calena Brown-Abel, Tao Lin, Sharad Awasthi, Kaifu Chen, Roy V Sillitoe, Jae-Il Park, Min Gyu Lee.

Spatiotemporal gene expression is the fundamental feature of cellular differentiation, including neuron differentiation. The epigenetic mechanism underlying spatiotemporal gene regulation during in vivo neuron differentiation remains largely unknown. Granule cells (GCs) constitute the vast majority of neurons in the cerebellum, which contains most of neurons in the brain. Here, we show that Atoh1-Cre-mediated knockout (ACKO) of Kmt2d encoding the lysine methyltransferase KMT2D (MLL4) in cerebellar GC lineage inhibits the transition of GC progenitors to GCs while cell non-autonomously affecting other cerebellar cells. Kmt2d ACKO impaired cerebellum-associated behaviors and caused facial peculiarity, microcephaly, and reduced body size in mice. KMT2D temporally activated neuronal differentiation programs in cerebellar GCs. KMT2D-mediated activation of the key neuronal transcription factor genes En2, Pax6, and Myt1l via super-enhancer/enhancer programming was critical for GC differentiation. These findings reveal a unique epigenetic mechanism in which KMT2D temporally orchestrates gene expression required for cerebellar GC differentiation by programming neuronal enhancers.

DOI: https://doi.org/10.1126/sciadv.adu7174
Nucleic Acids Res. 2025 Sep 23. pii: gkaf916. [Epub ahead of print]53(18):

Mammalian H4K16ac regulates the spatiotemporal order of genome replication rather than gene expression.

Marta Milan, Valeria Runfola, Manthan Patel, Lucia Falbo, Roberta Noberini, Chiara Soriani, Simona Rodighiero, Tiziana Bonaldi, Vincenzo Costanzo, Madapura M Pradeepa, Paola Scaffidi.

Histone acetylation is widely assumed to directly instruct gene activation. Among acetylated residues, H4K16ac is one of the most abundant modifications, conserved across all eukaryotes. Despite its established role in X-chromosome hyperactivation in Drosophila, its function in mammalian cells has remained elusive. Here, we show that in human somatic cells, H4K16ac does not substantially affect gene expression, but instead controls the spatiotemporal program of genome replication. By combining a meta-analysis of public datasets and perturbation experiments designed to minimize confounding effects, we found that H4K16ac is neither associated with nor required for transcriptional activity. Rather, H4K16ac depletion resulted in premature replication of heterochromatic regions and widespread alterations in replication timing across the genome. These defects were driven by the aberrant activation of cryptic replication origins at long terminal repeats-repetitive elements typically marked by H4K16ac and whose sequence context resembles that of canonical origins in euchromatic regions. Our findings reveal an unexpected role for one of the most prevalent chromatin modifications and uncover a new regulatory mechanism that safeguards genome replication fidelity.

DOI: https://doi.org/10.1093/nar/gkaf916
Sci Adv. 2025 Sep 26. 11(39): eadx7804

TOC1 phosphorylation disproportionally enhances chromatin binding at rhythmic gene promoters.

Jiapei Yan, Ying Zhang, Guoting Chen, Cuilin Gui, Zhangli Tu, Donglin Cao, Jing-Wen Yao, Xingwang Li, David E Somers.

Protein phosphorylation is a key regulatory mechanism in circadian systems. TIMING OF CAB EXPRESSION 1 (TOC1) is a core transcriptional repressor in the plant circadian system that is phosphorylated near its N terminus. Phenotype testing of TOC1 phosphosite mutants shows incomplete rescue of the short period toc1 mutant. We establish that TOC1 phosphorylation (particularly at S175) is necessary for optimal interaction with FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and PHYTOCHROME INTERACTING FACTOR 5 (PIF5) at the CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) promoter to down-regulate CCA1 expression. Expression of the closely related LATE ELONGATED HYPOCOTYL (LHY) also requires TOC1 but is independent of TOC1 phosphorylation, suggesting different TOC1-dependent gene repression mechanisms. We additionally show that TOC1 phosphorylation-dependent interactions at specific clock gene promoters selectively regulate these circadian system components more acutely than nonrhythmic genes. Our genome-wide analysis demonstrates that the TOC1 phosphostate is important for optimal chromatin presence and robust rhythmic gene expression.

DOI: https://doi.org/10.1126/sciadv.adx7804
Nat Methods. 2025 Sep 25.

Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance.

Christoph Geisenberger, Jeroen van den Berg, Vincent van Batenburg, Buys de Barbanson, Anna Lyubimova, Joe Verity-Legg, Xiufei Chen, Yibin Liu, Chun-Xiao Song, Jeroen de Ridder, Alexander van Oudenaarden.

DNA methylation and histone modifications encode epigenetic information. Recently, major progress was made to measure either mark at a single-cell resolution; however, a method for simultaneous detection is lacking, preventing study of their interactions. Here, to bridge this gap, we developed scEpi2-seq. Our technique provides a readout of histone modifications and DNA methylation at the single-cell and single-molecule level. Application in a cell line with the FUCCI cell cycle reporter system reveals how DNA methylation maintenance is influenced by the local chromatin context. In addition, profiling of H3K27me3 and DNA methylation in the mouse intestine yields insights into epigenetic interactions during cell type specification. Differentially methylated regions also demonstrated independent cell-type regulation in addition to H3K27me3 regulation, which reinforces that CpG methylation acts as an additional layer of control in facultative heterochromatin.

DOI: https://doi.org/10.1038/s41592-025-02847-4
Nucleic Acids Res. 2025 Sep 23. pii: gkaf964. [Epub ahead of print]53(18):

Coordinated control of genome-nuclear lamina interactions by topoisomerase 2B and lamin B receptor.

Tom van Schaik, Mikhail Magnitov, Marcel de Haas, Jeremie Breda, Elzo de Wit, Anna G Manjon, René H Medema, Henrike Johanna Gothe, Vassilis Roukos, Adam J Buckle, Catherine Naughton, Nick Gilbert, Bas van Steensel, Stefano G Manzo.

Lamina-associated domains (LADs) are megabase-sized genomic regions anchored to the nuclear lamina (NL). Factors controlling the interactions of the genome with the NL have largely remained elusive. Here, we identified DNA topoisomerase 2 beta (TOP2B) as a regulator of these interactions. TOP2B binds predominantly to inter-LAD (iLAD) chromatin and its depletion results in a partial loss of genomic partitioning between LADs and iLADs, suggesting that this enzyme might protect specific iLADs from interacting with the NL. TOP2B depletion affects LAD interactions with lamin B receptor (LBR) more than with lamins. LBR depletion phenocopies the effects of TOP2B depletion, despite the different positioning of the two proteins in the genome. This suggests a complementary mechanism for organizing the genome at the NL. Indeed, co-depletion of TOP2B and LBR causes partial LAD/iLAD inversion, reflecting changes typical of oncogene-induced senescence. We propose that a coordinated axis controlled by TOP2B in iLADs and LBR in LADs maintains the partitioning of the genome between the NL and the nuclear interior.

DOI: https://doi.org/10.1093/nar/gkaf964