bims-crepig 2025-05-04 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2025–05–04
twenty-two papers selected by
Connor Rogerson, University of Cambridge

The SAS chromatin-remodeling complex mediates inflorescence-specific chromatin accessibility for transcription factor binding.
Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation.
Bimodal specificity of TF-DNA recognition in embryonic stem cells.
Altering metabolism programs cell identity via NAD+-dependent deacetylation.
TAF2 condensation in nuclear speckles links basal transcription factor TFIID to RNA splicing factors.
Inferring differential protein binding from time-series chromatin accessibility data.
Chromatin-bound U2AF2 splicing factor ensures exon inclusion.
METTL3-dependent m6A RNA methylation regulates transposable elements and represses human naïve pluripotency through transposable element-derived enhancers.
PAF1C-mediated activation of CDK12/13 kinase activity is critical for CTD phosphorylation and transcript elongation.
Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS.
TF2TG: an online resource mining the potential gene targets of transcription factors in Drosophila.
scMultiMap: Cell-type-specific mapping of enhancers and target genes from single-cell multimodal data.
Tri-omic single-cell mapping of the 3D epigenome and transcriptome in whole mouse brains throughout the lifespan.
Quantification and potential functional relevance of binding cooperativity of adjacent transcription factors on DNA.
Essential angiosperm-specific subunits of HDA19 histone deacetylase complexes in Arabidopsis.
Atlas of nascent RNA transcripts reveals tissue-specific enhancer to gene linkages.
14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation.
RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates.
Histone tetrasome dynamics affects chromatin transcription.
S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis.
Chromosomal instability in human trophoblast stem cells and placentas.
Super RNA Pol II domains enhance minor ZGA through 3D interaction to ensure the integrity of major transcriptional waves in late-ZGA mammals.

Nucleic Acids Res. 2025 Apr 22. pii: gkaf316. [Epub ahead of print]53(8):

The SAS chromatin-remodeling complex mediates inflorescence-specific chromatin accessibility for transcription factor binding.

Jing Guo, Zhen-Zhen Liu, Xiao-Min Su, Yin-Na Su, Xin-Jian He.

While the role of transcription factors in flower development is well understood, the impact of chromatin remodeling on this process remains largely unclear. We conducted a comprehensive analysis to investigate the coordination of the SAS, BAS, and MAS-type SWI/SNF chromatin-remodeling complexes with transcription factors to regulate chromatin accessibility and gene transcription during flower development in Arabidopsis thaliana. Our findings indicate that the SAS complex binds to numerous genes related to flower development and is responsible for establishing chromatin accessibility of these genes in inflorescences. In contrast, the BAS and MAS complexes exhibit minimal involvement in regulating the accessibility of these genes. The SAS-bound genomic regions and the SAS-dependent accessible regions in infloresences are enriched with sites occupied by multiple MADS family transcription factors involved in flower development. Furthermore, we found that the SAS-dependent accessibility facilitates the binding of the MADS transcription factor AP1 to a subset of its target loci. This study highlights the dynamic role of the SAS complex in modulating the chromatin accessibility and genomic binding of transcription factors during plant development.

DOI: https://doi.org/10.1093/nar/gkaf316
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00404-8. [Epub ahead of print]44(5): 115633

Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation.

Jiabei Lian, Yachun An, Wenjing Wei, Yao Lu, Xiyu Zhang, Gongping Sun, Haiyang Guo, Longjin Xu, Xuena Chen, Huili Hu.

  Liver regeneration is a well-organized and phase-restricted process that involves chromatin remodeling and transcriptional alterations. However, the specific transcription factors (TFs) that act as key "switches" to initiate hepatocyte regeneration and organoid formation remain unclear. Comprehensive integration of RNA sequencing and ATAC sequencing reveals that ATF3 representing "Initiation_on" TF and ONECUT2 representing "Initiation_off" TF transiently modulate the occupancy of target promoters to license liver cells for regeneration. Knockdown of Atf3 or overexpression of Onecut2 not only reduces organoid formation but also delays tissue-damage repair after PHx or CCl4 treatment. Mechanistically, we demonstrate that ATF3 binds to the promoter of Slc7a5 to activate mTOR signals while the Hmgcs1 promoter loses ONECUT2 binding to facilitate regenerative initiation. The results identify the mechanism for initiating regeneration and reveal the remodeling of transcriptional landscapes and chromatin accessibility, thereby providing potential therapeutic targets for liver diseases with regenerative defects.

Keywords:  CP: Molecular biology; CP: Stem cell research; chromatin accessibility; hepatocyte organoids; regenerative initiation; transcription factors

DOI:  https://doi.org/10.1016/j.celrep.2025.115633
Nucleic Acids Res. 2025 Apr 22. pii: gkaf333. [Epub ahead of print]53(8):

Bimodal specificity of TF-DNA recognition in embryonic stem cells.

Michael Povolotskii, Maor Yehezkehely, Oren Ram, David B Lukatsky.

Transcription factors (TFs) bind genomic DNA regulating gene expression and developmental programs in embryonic stem cells (ESCs). Even though comprehensive genome-wide molecular maps for TF-DNA binding are experimentally available for key pluripotency-associated TFs, the understanding of molecular design principles responsible for TF-DNA recognition remains incomplete. Here, we show that binding preferences of key pluripotency TFs, such as Pou5f1 (Oct4), Smad1, Otx2, Srf, and Nanog, exhibit bimodality in the local GC-content distribution. Sequence-dependent binding specificity of these TFs is distributed across three major contributions. First, local GC-content is dominant in high-GC-content regions. Second, recognition of specific k-mers is predominant in low-GC-content regions. Third, short tandem repeats (STRs) are highly predictive in both low- and high-GC-content regions. In sharp contrast, the binding preferences of c-Myc are exclusively dominated by local GC-content and STRs in high-GC-content genomic regions. We demonstrate that the transition in the TF-DNA binding landscape upon ESC differentiation is regulated by the concentration of c-Myc, which forms a bivalent c-Myc-Max heterotetramer upon promoter binding, competing with key pluripotency factors such as Smad1. Finally, a direct interaction between c-Myc and key pluripotency factors is not required to achieve this transition.

DOI: https://doi.org/10.1093/nar/gkaf333
EMBO J. 2025 Apr 25.

Altering metabolism programs cell identity via NAD+-dependent deacetylation.

Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, Joshua M Brickman.

  Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.

Keywords:  Aging; Enhancers; Metabolism; Pluripotency; Sirtuins

DOI:  https://doi.org/10.1038/s44318-025-00417-0
Cell Rep. 2025 Apr 26. pii: S2211-1247(25)00387-0. [Epub ahead of print]44(5): 115616

TAF2 condensation in nuclear speckles links basal transcription factor TFIID to RNA splicing factors.

Tanja Bhuiyan, Niccolò Arecco, Paulina Karen Mendoza Sanchez, Juhyeong Kim, Carsten Schwan, Sophie Weyrauch, Sheikh Nizamuddin, Andrea Prunotto, Mehmet Tekman, Martin L Biniossek, Bettina Knapp, Stefanie Koidl, Friedel Drepper, Pitter F Huesgen, Robert Grosse, Thorsten Hugel, Sebastian J Arnold.

  TFIID is an essential basal transcription factor, crucial for RNA polymerase II (pol II) promoter recognition and transcription initiation. The TFIID complex consists of the TATA binding protein (TBP) and 13 TBP-associated factors (TAFs) that contain intrinsically disordered regions (IDRs) with currently unknown functions. Here, we show that a conserved IDR drives TAF2 to nuclear speckle condensates independently of other TFIID subunits. Quantitative mass spectrometry analyses reveal TAF2 proximity to RNA splicing factors including specific interactions of the TAF2 IDR with SRRM2 in nuclear speckles. Deleting the IDR from TAF2 does not majorly impact global gene expression but results in changes of alternative splicing events. Further, genome-wide binding analyses suggest that the TAF2 IDR impedes TAF2 promoter association by guiding TAF2 to nuclear speckles. This study demonstrates that an IDR within the large multiprotein complex TFIID controls nuclear compartmentalization and thus links distinct molecular processes, namely transcription initiation and RNA splicing.

Keywords:  CP: Molecular biology; SRRM2; TAF2; TFIID; alternative splicing; biomolecular condensates; intrinsically disordered regions; nuclear bodies; nuclear speckles; transcription

DOI:  https://doi.org/10.1016/j.celrep.2025.115616
Bioinform Adv. 2025 ;5(1): vbaf080

Inferring differential protein binding from time-series chromatin accessibility data.

Sneha Mitra, Alexander J Hartemink.

Motivation: Due to internal and external factors, the epigenomic landscape is constantly changing in ways that are linked to changes in gene expression. Chromatin accessibility data, such as MNase-seq, provide valuable insights into this landscape and have been used to compute chromatin occupancy profiles. Multiple datasets generated over time or under different conditions can thus be used to study dynamic changes in chromatin occupancy across the genome.
Results: Our existing model, RoboCOP, computes a genome-wide chromatin occupancy profile for nucleosomes and hundreds of transcription factors. Here, we present a new method called DynaCOP that takes multiple chromatin occupancy profiles and uses them to generate a series of nucleosome-guided difference profiles. These profiles identify differentially binding transcription factors and reveal changes in nucleosome occupancy and positioning. We apply DynaCOP to chromatin occupancy profiles derived from deeply sequenced time-series MNase-seq data to study differential chromatin occupancy in the yeast genome under cadmium stress. We find strong correlations between the observed chromatin changes and changes in transcription.
Availability and implementation: https://github.com/HarteminkLab/RoboCOP.

DOI: https://doi.org/10.1093/bioadv/vbaf080
Mol Cell. 2025 Apr 28. pii: S1097-2765(25)00316-8. [Epub ahead of print]

Chromatin-bound U2AF2 splicing factor ensures exon inclusion.

Weifang Wu, Kami Ahmad, Steven Henikoff.

  Most mRNA splicing occurs co-transcriptionally, but it is unclear how splicing factors accurately select exons for inclusion. Using CUT&RUN profiling in K562 cells, we demonstrate that three splicing factors-SF3B1, U2AF1, and U2AF2-bind near active promoters of intron-containing and intronless genes, implying their association with the general transcriptional machinery. RNase A treatment reduces factor binding at promoters, indicating that these proteins interact with nascent transcripts. Strikingly, the U2AF2 protein also accumulates throughout intron-containing gene bodies and requires histone H3-lysine36 trimethylation but not nascent transcripts or persistent RNA polymerase II. Chromatin-bound U2AF2 preferentially binds to exons of highly expressed, exon-dense genes, with greater occupancy at exons skipped after U2AF2 knockdown, suggesting that U2AF2 enhances exon selection accuracy. U2AF2-targeted genes include those encoding splicing factors, where it improves splicing accuracy and efficiency. Our findings provide a mechanistic basis for the homeostatic regulation of efficient co-transcriptional splicing by chromatin-bound U2AF2.

Keywords:  H3K36me3; RNA polymerase II; SF3B155; U2AF35; U2AF65; co-transcriptional RNA splicing; exon definition

DOI:  https://doi.org/10.1016/j.molcel.2025.04.013
Nucleic Acids Res. 2025 Apr 22. pii: gkaf349. [Epub ahead of print]53(8):

METTL3-dependent m6A RNA methylation regulates transposable elements and represses human naïve pluripotency through transposable element-derived enhancers.

Weiyu Zhang, Haifeng Fu, Yunying Huang, Ming Zeng, Xiangyu Ouyang, Xiao Wang, Degong Ruan, Liyang Ma, Xinning Hu, Jilong Guo, Justin W Galardi, Gordon Dougan, William S B Yeung, Lei Li, Jianqiao Liu, Cedric Feschotte, Pentao Liu.

N 6-methyladenosine (m6A) is the most prevalent messenger RNA modification with diverse regulatory roles in mammalian cells. While its functions are well-documented in mouse embryonic stem cells (mESCs), its role in human pluripotent stem cells (hPSCs) remains to be fully explored. METTL3 is the main enzyme responsible for m6A deposition. Here, using a METTL3 inducible knockout (iKO) system, we uncovered that, unlike in mESCs, METTL3 was indispensable for hPSC maintenance. Importantly, loss of METTL3 caused significant upregulation of pluripotency factors including naïve pluripotency genes and failure to exit pluripotency, thus impairing stem cell differentiation towards both embryonic and extraembryonic cell lineages. Mechanistically, METTL3 iKO in hPSCs promoted expression and enhancer activities of two primate-specific transposable elements (TEs), SVA_D and HERVK/LTR5_Hs. At SVA_D elements, loss of METTL3 leads to reduced H3K9me3 deposition. On the other hand, the activation of LTR5_Hs in the METTL3 iKO cells is accompanied by increased chromatin accessibility and binding pluripotency factors. The activated SVA_D and LTR5_Hs elements can act as enhancers and promote nearby naïve gene expression by directly interacting with their promoters. Together these findings reveal that METTL3-dependent m6A RNA methylation plays critical roles in suppressing TE expression and in regulating the human pluripotency network.

DOI: https://doi.org/10.1093/nar/gkaf349
Mol Cell. 2025 Apr 24. pii: S1097-2765(25)00315-6. [Epub ahead of print]

PAF1C-mediated activation of CDK12/13 kinase activity is critical for CTD phosphorylation and transcript elongation.

David Lopez Martinez, Izabela Todorovski, Melvin Noe Gonzalez, Charlotte Rusimbi, Daniel Blears, Nessrine Khallou, Zhong Han, A Barbara Dirac-Svejstrup, Jesper Q Svejstrup.

  The transcription cycle is regulated by dynamic changes in RNA polymerase II (RNAPII) C-terminal domain (CTD) phosphorylation, which are crucial for gene expression. However, the mechanisms regulating the transcription-specific cyclin-dependent kinases (CDKs) during the transcription cycle remain poorly understood. Here, we show that human CDK12 co-phosphorylates CTD Serine2 and Serine5. This di-phosphorylated Serine2-Serine5 CTD mark may then act as a precursor for Serine2 mono-phosphorylated CTD through Serine5 de-phosphorylation. Notably, CDK12 is specifically regulated by association with the elongation-specific factor PAF1 complex (PAF1C), in which the CDC73 subunit contains a metazoan-specific peptide motif, capable of allosteric CDK12/cyclin K activation. This motif is essential for cell proliferation and required for normal levels of CTD phosphorylation in chromatin, and for transcript elongation, particularly across long human genes. Together, these findings provide insight into the mechanisms governing RNAPII phospho-CTD dynamics that ensure progression through the human transcription cycle.

Keywords:  C-terminal domain; CDC73; CDK12; CDK13; CTD; Paf1 complex; RNA polymerase II; cyclin K; phosphorylation; transcript elongation

DOI:  https://doi.org/10.1016/j.molcel.2025.04.012
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00390-0. [Epub ahead of print]44(5): 115619

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS.

Shilpa S Dhar, Calena Brown, Ali Rizvi, Lauren Reed, Sivareddy Kotla, Constantin Zod, Janak Abraham, Jun-Ichi Abe, Veena Rajaram, Kaifu Chen, Min Gyu Lee.

  The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in many cancers, including medulloblastoma (MB). Notably, heterozygous KMT2D loss frequently occurs in MB and other cancers. However, its oncogenic role remains largely uncharacterized. Here, we show that heterozygous Kmt2d loss in murine cerebellar regions promotes MB genesis driven by heterozygous loss of the MB-suppressor gene Ptch via the upregulation of tumor-promoting programs (e.g., oxidative phosphorylation [OXPHOS]). Downregulation of the transcription-repressive tumor suppressor NCOR2 by heterozygous Kmt2d loss, along with Ptch+/--increased MYCN, upregulated tumor-promoting genes. Heterozygous Kmt2d loss substantially diminished enhancer marks (H3K4me1 and H3K27ac) and the H3K4me3 signature, including those for Ncor2. Combinatory pharmacological inhibition of the enhancer-decommissioning H3K4 demethylase LSD1 and OXPHOS significantly reduced the tumorigenicity of MB cells bearing heterozygous Kmt2d loss. Our findings suggest the molecular and epigenetic pathogenesis underlying the MB-promoting effect of heterozygous KMT2D loss.

Keywords:  CP: Cancer; CP: Metabolism; KMT2D; LSD1; NCOR2; OXPHOS; enhancer; epigenetic modifier; heterozygous loss; histone methyltransferase; medulloblastoma; tumor suppressor

DOI:  https://doi.org/10.1016/j.celrep.2025.115619
Genetics. 2025 May 02. pii: iyaf082. [Epub ahead of print]

TF2TG: an online resource mining the potential gene targets of transcription factors in Drosophila.

Yanhui Hu, Jonathan Rodiger, Yifang Liu, Chenxi Gao, Ying Liu, Mujeeb Qadiri, Austin Veal, Martha L Bulyk, Norbert Perrimon.

  Sequence-specific transcription factors (TFs) are key regulators of many biological processes, controlling the expression of their target genes through binding to the cis- regulatory regions such as promoters and enhancers. Each TF has unique DNA binding site motifs, and large-scale experiments have been conducted to characterize TF-DNA binding preferences. However, no comprehensive resource currently integrates these datasets for Drosophila. To address this need, we developed TF2TG ("transcription factor" to "target gene"), a comprehensive resource that combines both in vitro and in vivo datasets to link transcription factors (TFs) to their target genes based on TF-DNA binding preferences along with the protein-protein interaction data, tissue-specific transcriptomic data, and chromatin accessibility data. Although the genome offers numerous potential binding sites for each TF, only a subset is actually bound in vivo, and of these, only a fraction is functionally relevant. For instance, some TFs bind to their specific sites due to synergistic interactions with other factors nearby. This integration provides users with a comprehensive list of potential candidates as well as aids users in ranking candidate genes and determining condition-specific TF binding for studying transcriptional regulation in Drosophila.

Keywords:  ChIP-Seq; Drosophila; FlyBase; TF motif; Transcription factors; protein complex; transcriptional regulation

DOI:  https://doi.org/10.1093/genetics/iyaf082
Nat Commun. 2025 Apr 26. 16(1): 3941

scMultiMap: Cell-type-specific mapping of enhancers and target genes from single-cell multimodal data.

Chang Su, Dongsoo Lee, Peng Jin, Jingfei Zhang.

Mapping enhancers and target genes in disease-related cell types provides critical insights into the functional mechanisms of genome-wide association studies (GWAS) variants. Single-cell multimodal data, which measure gene expression and chromatin accessibility in the same cells, enable the cell-type-specific inference of enhancer-gene pairs. However, this task is challenged by high data sparsity, sequencing depth variation, and the computational burden of analyzing a large number of pairs. We introduce scMultiMap, a statistical method that infers enhancer-gene association from sparse multimodal counts using a joint latent-variable model. It adjusts for technical confounding, permits fast moment-based estimation and provides analytically derived p-values. In blood and brain data, scMultiMap shows appropriate type I error control, high statistical power, and computational efficiency (1% of existing methods). When applied to Alzheimer's disease (AD) data, scMultiMap gives the highest heritability enrichment in microglia and reveals insights into the regulatory mechanisms of AD GWAS variants.

DOI: https://doi.org/10.1038/s41467-025-59306-z
Nat Methods. 2025 Apr 29.

Tri-omic single-cell mapping of the 3D epigenome and transcriptome in whole mouse brains throughout the lifespan.

Haoxi Chai, Xingyu Huang, Guangzhou Xiong, Jiaxiang Huang, Katarzyna Karolina Pels, Lingyun Meng, Jin Han, Dongmei Tang, Guanjing Pan, Liang Deng, Qin Xiao, Xiaotao Wang, Meng Zhang, Krzysztof Banecki, Dariusz Plewczynski, Chia-Lin Wei, Yijun Ruan.

Exploring the genomic basis of transcriptional programs has been a long-standing research focus. Here we report a single-cell method, ChAIR, to map chromatin accessibility, chromatin interactions and RNA expression simultaneously. After validating in cultured cells, we applied ChAIR to whole mouse brains and delineated the concerted dynamics of epigenome, three-dimensional (3D) genome and transcriptome during maturation and aging. In particular, gene-centric chromatin interactions and open chromatin states provided 3D epigenomic mechanism underlying cell-type-specific transcription and revealed spatially resolved specificity. Importantly, the composition of short-range and ultralong chromatin contacts in individual cells is remarkably correlated with transcriptional activity, open chromatin state and genome folding density. This genomic property, along with associated cellular properties, differs in neurons and non-neuronal cells across different anatomic regions throughout the lifespan, implying divergent nuclear mechano-genomic mechanisms at play in brain cells. Our results demonstrate ChAIR's robustness in revealing single-cell 3D epigenomic states of cell-type-specific transcription in complex tissues.

DOI: https://doi.org/10.1038/s41592-025-02658-7
Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2422555122

Quantification and potential functional relevance of binding cooperativity of adjacent transcription factors on DNA.

Xinyao Wang, Chen Xie, Ke Shen, Dubai Li, Xiaoliang Sunney Xie.

  In eukaryotes, the expression of specific genes is regulated by a combination of transcription factors (TFs) bound on regulatory regions of the genomic DNA (promoters and enhancers). Recent advances in genomic sequencing technology have enabled the measurements of TFs' footprints and binding affinities on DNA at the single-molecule level, facilitating the probing of binding cooperativity among adjacent TFs. This necessitates quantitative descriptions of TFs' binding cooperativity and understanding of its potential functional relevance. In this study, we show that the binding cooperativities between two adjacent TFs can be quantified by the [Formula: see text] coefficient, which can be experimentally determined. Under thermodynamic equilibrium, the binding affinities of two TFs can either increase together (positive cooperativity) or decrease together (negative cooperativity), but not in opposing directions (one increases while the other decreases). Within the framework of thermodynamics, we investigate the functional relevance of cooperativity. The functional relevance of positive cooperativity, which has been extensively discussed in the literature, is the sigmoidal binding curve around a TF concentration threshold (analogous to oxygen binding to hemoglobin), whereas the functional relevance of negative cooperativity is twofold. First, mutual exclusion of the two TFs enables bidirectional gene switching, akin to the CI-Cro system in phage [Formula: see text]. Second, while TFs often exhibit intranuclear concentration fluctuations, negative binding cooperativity assures fast TF dissociation from DNA and hence rapid response for gene expression regulation. Furthermore, the nonequilibrium steady states of living cells can lead to either positive or negative cooperativity, which can also be quantified by the [Formula: see text] coefficient.

Keywords:  binding affinity; functional relevance; negative cooperativity; nonequilibrium steady state; transcription factor

DOI:  https://doi.org/10.1073/pnas.2422555122
EMBO J. 2025 Apr 28.

Essential angiosperm-specific subunits of HDA19 histone deacetylase complexes in Arabidopsis.

Na Liu, Jia-Xin Li, Dan-Yang Yuan, Yin-Na Su, Pei Zhang, Qi Wang, Xiao-Min Su, Lin Li, Haitao Li, She Chen, Xin-Jian He.

  Although the Arabidopsis thaliana RPD3-type histone deacetylase HDA19 and its close homolog HDA6 participate in SIN3-type histone deacetylase complexes, they display distinct biological roles, with the reason for these differences being poorly understood. This study identifies three angiosperm-specific HDA19-interacting homologous proteins, termed HDIP1, HDIP2, and HDIP3 (HDIP1/2/3). These proteins interact with HDA19 and other conserved histone deacetylase complex components, leading to the formation of HDA19-containing SIN3-type complexes, while they are not involved in the formation of HDA6-containing complexes. While mutants of conserved SIN3-type complex components show phenotypes divergent from the hda19 mutant, the hdip1/2/3 mutant closely phenocopies the hda19 mutant with respect to development, abscisic acid response, and drought stress tolerance. Genomic and transcriptomic analyses indicate that HDIP1/2/3 and HDA19 co-occupy chromatin and jointly repress gene transcription, especially for stress-related genes. An α-helix motif within HDIP1 has the capacity to bind to nucleosomes and architectural DNA, and is required for its function in Arabidopsis plants. These findings suggest that the angiosperm SIN3-type complexes have evolved to include additional subunits for the precise regulation of histone deacetylation and gene transcription.

Keywords:  Development; HDA19; Histone Deacetylation; Stress Response; Transcriptional Repression

DOI:  https://doi.org/10.1038/s44318-025-00445-w
BMC Genomics. 2025 Apr 25. 26(1): 406

Atlas of nascent RNA transcripts reveals tissue-specific enhancer to gene linkages.

Rutendo F Sigauke, Lynn Sanford, Zachary L Maas, Taylor Jones, Jacob T Stanley, Hope A Townsend, Mary A Allen, Robin D Dowell.

  Gene transcription is controlled and modulated by regulatory regions, including enhancers and promoters. These regions are abundant in non-coding bidirectional transcription that results in generally unstable RNA. Using nascent RNA transcription data across hundreds of human samples, we identified over 800,000 regions containing bidirectional transcription. We then identify tissue specific, highly correlated transcription between bidirectional and gene regions. The identified correlated pairs, a bidirectional region and a gene, are enriched for disease associated SNPs and often supported by independent 3D data. We present these resources as a database called DBNascent ( https://nascent.colorado.edu/ ) which serves as a resource for future studies into gene regulation, enhancer associated RNAs, and transcription factors.

Keywords:  Bidirectional transcription; Enhancer RNA; Nascent RNA sequencing

DOI:  https://doi.org/10.1186/s12864-025-11568-z
Mol Metab. 2025 Apr 28. pii: S2212-8778(25)00066-3. [Epub ahead of print] 102159

14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation.

Rial Sa, You Z, Vivoli A, Paré F, Sean D, Amal Al-Khoury, Lavoie G, Civelek M, A Martinez-Sanchez, Roux Pp, Durcan Tm, Lim Ge.

  We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but the temporal specificity of its action during adipocyte differentiation remains unclear. To decipher if 14-3-3ζ exerts its regulatory functions on mature adipocytes or on adipose precursor cells (APCs), we generated Adipoq14-3-3ζKO and Pdgfra14-3-3ζKO mouse models. Our findings revealed a pivotal role for 14-3-3ζ in APC differentiation, whereby male and female Pdgfra14-3-3ζKO mice display impaired or potentiated weight gain, respectively, as well as fat mass. To better understand how 14-3-3ζ regulates the adipogenic transcriptional program in APCs, CRISPR-Cas9 was used to generate tandem affinity purification (TAP)-tagged 14-3-3ζ-expressing 3T3-L1 preadipocytes. Using these cells, we examined if the 14-3-3ζ nuclear interactome is enriched with adipogenic regulators during differentiation. Regulators of chromatin remodeling, such as DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), were enriched in the nuclear interactome of 14-3-3ζ, and their activities were impacted upon 14-3-3ζ depletion. Enhancing DNMT activity with S-Adenosyl methionine rescued the differentiation of 3T3-L1 cells after 14-3-3ζ depletion. The interactions between 14-3-3ζ and chromatin-modifying enzymes suggested that 14-3-3ζ may control chromatin remodeling during adipogenesis, and this was confirmed by ATAC-seq, which revealed that 14-3-3ζ depletion impacted the accessibility of up to 1,244 chromatin regions corresponding in part to adipogenic genes, promoters, and enhancers during the initial stages of adipogenesis. Moreover, 14-3-3ζ-dependent chromatin accessibility was found to correlate with the expression of key adipogenic genes. Altogether, our study establishes 14-3-3ζ as a crucial epigenetic regulator of adipogenesis and highlights the usefulness of deciphering the nuclear 14-3-3ζ interactome to identify novel pro-adipogenic factors and pathways.

Keywords:  14-3-3ζ; adipogenesis; adipogenic genes; chromatin accessibility; energy homeostasis; epigenetic regulation

DOI:  https://doi.org/10.1016/j.molmet.2025.102159
Cell. 2025 Apr 23. pii: S0092-8674(25)00404-0. [Epub ahead of print]

RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates.

Heankel Lyons, Prashant Pradhan, Gopinath Prakasam, Shubham Vashishtha, Xiang Li, Mikayla Eppert, Christy Fornero, Vanina T Tcheuyap, Kathleen McGlynn, Ze Yu, Dinesh Ravindra Raju, Prasad R Koduru, Chao Xing, Payal Kapur, James Brugarolas, Benjamin R Sabari.

  Condensates regulate transcription by selectively compartmentalizing biomolecules, yet the rules of specificity and their relationship to function remain enigmatic. To identify rules linked to function, we leverage the genetic selection bias of condensate-promoting oncofusions. Focusing on the three most frequent oncofusions driving translocation renal cell carcinoma, we find that they promote the formation of condensates that activate transcription by gain-of-function RNA polymerase II partitioning through a shared signature of elevated π and π-interacting residues and depletion of aliphatic residues. This signature is shared among a broad set of DNA-binding oncofusions associated with diverse cancers. We find that this signature is necessary and sufficient for RNA polymerase II partitioning, gene activation, and cancer cell phenotypes. Our results reveal that dysregulated condensate specificity is a shared molecular mechanism of diverse oncofusions, highlighting the functional role of condensate composition and the power of disease genetics in investigating relationships between condensate specificity and function.

Keywords:  Pol II-CTD; biomolecular condensates; condensate specificity; oncofusions; selective partitioning; transcription

DOI:  https://doi.org/10.1016/j.cell.2025.04.002
Nucleic Acids Res. 2025 Apr 22. pii: gkaf356. [Epub ahead of print]53(8):

Histone tetrasome dynamics affects chromatin transcription.

Xiangyan Shi, Anastasiia S Fedulova, Elena Y Kotova, Natalya V Maluchenko, Grigoriy A Armeev, Qinming Chen, Chinmayi Prasanna, Anastasia L Sivkina, Alexey V Feofanov, Mikhail P Kirpichnikov, Lars Nordensköld, Alexey K Shaytan, Vasily M Studitsky.

During various DNA-centered processes in the cell nucleus, the minimal structural units of chromatin organization, nucleosomes, are often transiently converted to hexasomes and tetrasomes missing one or both H2A/H2B histone dimers, respectively. However, the structural and functional properties of the subnucleosomes and their impact on biological processes in the nuclei are poorly understood. Here, using biochemical approaches, molecular dynamics simulations, single-particle Förster resonance energy transfer microscopy, and nuclear magnetic resonance spectroscopy, we have shown that, surprisingly, removal of both dimers from a nucleosome results in much higher mobility of both histones and DNA in the tetrasome. Accordingly, DNase I footprinting shows that DNA-histone interactions in tetrasomes are greatly compromised, resulting in formation of a much lower barrier to transcribing RNA polymerase II than nucleosomes. The data suggest that tetrasomes are remarkably dynamic structures and their formation can strongly affect various biological processes.

DOI: https://doi.org/10.1093/nar/gkaf356
Nat Commun. 2025 Apr 27. 16(1): 3953

S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis.

Ashima Sakhuja, Ritobrata Bhattacharyya, Yash Tushar Katakia, Shyam Kumar Ramakrishnan, Srinjoy Chakraborty, Hariharan Jayakumar, Shailesh Mani Tripathi, Niyati Pandya Thakkar, Sumukh Thakar, Sandeep Sundriyal, Shibasish Chowdhury, Syamantak Majumder.

Nitric oxide (NO), a versatile bio-active molecule modulates cellular functions through diverse mechanisms including S-nitrosylation of proteins. Herein, we report S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells, which interplays with its stability and functions. We detect a significant reduction in H3K27me3 upon S-nitrosylation of EZH2 as contributed by the early dissociation of SUZ12 from the PRC2. Moreover, S-nitrosylation of EZH2 causes its cytosolic translocation, ubiquitination, and degradation. Further analysis reveal S-nitrosylation of cysteine 329 induces EZH2 instability, whereas S-nitrosylation of cysteine 700 abrogates its catalytic activity. We further show that S-nitrosylation-dependent regulation of EZH2 maintains endothelial homeostasis in both physiological and pathological settings. Molecular dynamics simulation reveals the inability of SUZ12 to efficiently bind to the SAL domain of EZH2 upon S-nitrosylation. Taken together, our study reports S-nitrosylation-dependent regulation of EZH2 and its associated PRC2 complex, thereby influencing the epigenetics of endothelial homeostasis.

DOI: https://doi.org/10.1038/s41467-025-59003-x
Nat Commun. 2025 Apr 25. 16(1): 3918

Chromosomal instability in human trophoblast stem cells and placentas.

Danyang Wang, Andrew Cearlock, Katherine Lane, Chongchong Xu, Ian Jan, Stephen McCartney, Ian Glass, Rajiv McCoy, Min Yang.

The human placenta, a unique tumor-like organ, is thought to exhibit rare aneuploidy associated with adverse pregnancy outcomes. Discrepancies in reported aneuploidy prevalence in placentas stem from limitations in modeling and detection methods. Here, we use isogenic trophoblast stem cells (TSCs) derived from both naïve and primed human pluripotent stem cells (hPSCs) to reveal the spontaneous occurrence of aneuploidy, suggesting chromosomal instability (CIN) as an inherent feature of the trophoblast lineage. We identify potential pathways contributing to the occurrence and tolerance of CIN, such as autophagy, which may support the survival of aneuploid cells. Despite extensive chromosomal abnormalities, TSCs maintain their proliferative and differentiation capacities. These findings are further validated in placentas, where we observe a high prevalence of heterogeneous aneuploidy across trophoblasts, particularly in invasive extravillous trophoblasts. Our study challenges the traditional view of aneuploidy in the placenta and provides insights into the implications of CIN in placental function.

DOI: https://doi.org/10.1038/s41467-025-59245-9
Cell Genom. 2025 Apr 29. pii: S2666-979X(25)00112-0. [Epub ahead of print] 100856

Super RNA Pol II domains enhance minor ZGA through 3D interaction to ensure the integrity of major transcriptional waves in late-ZGA mammals.

Jingcheng Zhang, Hengkuan Li, Linmi Li, Jie Wu, Linjie Song, Xin Liu, Zhangyuan Pan, Chuan Zhou, Wenying Li, Zixiao Liu, Mei Jiao, Mingyang Hu, Zhenyu Dong, Hexu Zhang, Binqiang Shi, Yong Wang, Debao Wang, Benjamin Carter, Shuhong Zhao, Gang Ren, Yunxia Zhao, Yong Zhang.

  Zygotic genome activation (ZGA) occurs at distinct stages across mammals, with mice initiating ZGA at the 2-cell stage and bovines and humans activating the process in the 4- to 8-cell stages. RNA polymerase II (RNA Pol II) gradually initiates ZGA in mice, but regulation in late-ZGA species remains unclear. Here, RNA Pol II profiling in bovine embryos identified strong intergenic clusters that boost minor ZGA gene expression via chromatin interactions and are named super RNA Pol II domains (SPDs). CRISPRi perturbation of SPDs in bovine embryos decreases the expression of minor ZGA genes, whereas the knockdown of these genes disrupts major ZGA and embryogenesis. Rapid enhancement of minor ZGA genes also occurs in human embryos. Alternatively, mouse and porcine oocytes precociously express these minor ZGA genes without SPDs. Thus, SPDs appear to be an adaptation in bovine embryos, promoting minor ZGA gene expression to comparable levels as early-ZGA species, illuminating species-specific regulation of ZGA timing.

Keywords:  3D interaction; RNA Pol II; SPDs; ZGA pace; interspecies comparison; zygotic genome activation

DOI:  https://doi.org/10.1016/j.xgen.2025.100856