bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–06–22
twenty-one papers selected by
Connor Rogerson, University of Cambridge
  1. H2A.Z is essential for oocyte maturation and fertility in female mouse.
  2. CRAMP1 drives linker histone expression to enable Polycomb repression.
  3. Coordinated action of multiple active histone modifications shapes the zygotic genome activation in teleost embryos.
  4. Cohesin supercoils DNA during loop extrusion.
  5. Multiple transactivation domains of EZH2 bind to the TAZ2 domain of p300 and stimulate acetyltransferase function of p300.
  6. Bivalent chromatin instructs lineage specification during hematopoiesis.
  7. SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
  8. Loop Catalog: a comprehensive HiChIP database of human and mouse samples.
  9. Divergence in a eukaryotic transcription factor's co-TF dependence involves multiple intrinsically disordered regions.
  10. CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance.
  11. Dynamic kissing model for enhancer-promoter communication on the surface of transcriptional condensates.
  12. Switchable RNA motifs for dynamic transcriptional control of RNA condensates.
  13. H2A.Z reinforces maternal H3K4me3 formation and is essential for meiotic progression in mouse oocytes.
  14. Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer.
  15. In vivo mapping of mutagenesis sensitivity of human enhancers.
  16. Repeated duplications and losses shaped SMC complex evolution from archaeal ancestors to modern eukaryotes.
  17. Induction of the zinc finger transcription factor GATA2 promotes kidney inflammation-related gene expression.
  18. Mechanisms driving functional divergence of transcription factor paralogs.
  19. Histone deacetylation as a landmark for Sgo2 relocation from centromeres to subtelomeres during interphase.
  20. Polycomb Repressive Complex 2 facilitates the transition from heterotrophy to photoautotrophy during seedling emergence.
  21. KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.
  1. Nat Struct Mol Biol. 2025 Jun 13.
    H2A.Z is essential for oocyte maturation and fertility in female mouse.
    Qianhua Xu, Chunyi Huang, Jia Ming, Xukun Lu, Ling Liu, Zhenhai Du, Zhen Chen, Jie Na, Guohong Li, Yunlong Xiang, Yu Zhang, Wei Xie.
      Oocyte maturation is essential for both gametogenesis and early development, when large amounts of transcripts are produced without DNA replication. Histone variants, which can be incorporated at cis-regulatory elements in a replication-independent manner, are naturally suited for such regulation. However, their roles during mammalian oocyte maturation remain elusive. Here we show that oocyte-specific depletion of H2A.Z, an evolutionarily conserved histone variant, in female mice results in profound epigenetic and transcriptional alterations, impedes resumption of oocyte meiosis II and causes infertility. Mechanistically, H2A.Z in mouse oocytes is incorporated into chromatin at active promoters and putative enhancers. Interestingly, H2A.Z is depleted from CG-rich silenced promoters, including poised Polycomb target genes, in fully grown oocytes (FGOs), unlike what occurs in growing oocytes, early embryos and mouse embryonic stem cells. In FGOs, the presence of H2A.Z correlates with histone acetylation, except in regions marked by DNA methylation and H3K36me3. Depletion of H2A.Z leads to impaired activities of a subset of promoters and enhancers, correlated with defective gene expression. Consistent with a role in gene activation, H2A.Z in FGOs is widely acetylated at the promoters and enhancers. Together, our findings uncover an essential role of H2A.Z in mammalian oocyte maturation and female fertility.
    DOI:  https://doi.org/10.1038/s41594-025-01580-y
  2. Mol Cell. 2025 Jun 10. pii: S1097-2765(25)00470-8. [Epub ahead of print]
    CRAMP1 drives linker histone expression to enable Polycomb repression.
    Rachael E Matthews, Joshua Miguel C Danac, Emily L Naden, Laura E Farleigh Smith, Sri Lestari, Akhila Gungi, Alex Appert, Toby Buttress, Ankit Verma, Oliver Sinclair, Faye Chong, John Suberu, Robin Antrobus, Boyan Bonev, Mark A Dawson, Adam J Reid, Richard T Timms, Julie Ahringer, Iva A Tchasovnikarova.
      In contrast to the well-understood role of core histones in DNA packaging, the function of the linker histone (H1) remains enigmatic. Challenging the prevailing view that linker histones are a general feature of heterochromatin, here we show a critical requirement for H1 in Polycomb repressive complex 2 (PRC2) function. A CRISPR-Cas9 genetic screen using a fluorescent PRC2 reporter identified an essential role for the poorly characterized gene CRAMP1 in PRC2-mediated repression. CRAMP1 localizes to the promoters of expressed H1 genes and positively regulates their transcription. CRAMP1 ablation simultaneously depletes all linker histones, which results in selective decompaction of H3K27me3-marked loci and derepression of PRC2 target genes without concomitant loss of PRC2 occupancy or enzymatic activity. Strikingly, we find that linker histones preferentially localize to genomic loci marked by H3K27me3 across diverse cell types and organisms. Altogether, these data demonstrate a prominent role for linker histones in epigenetic repression by PRC2.
    Keywords:  H1; PRC2; Polycomb; chromatin; epigenetic silencing; epigenetics; heterochromatin; histone; linker histone
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.031
  3. Nat Commun. 2025 Jun 16. 16(1): 5222
    Coordinated action of multiple active histone modifications shapes the zygotic genome activation in teleost embryos.
    Hiroto S Fukushima, Hiroyuki Takeda.
      Zygotic genome activation (ZGA) is a critical developmental milestone characterized by the rapid and simultaneous activation of genome-widely silenced chromatin. Various active histone modifications accumulate upon ZGA and have long been implicated in ZGA. However, their biological relevance still remains unclear. Here, we comprehensively examined the functional significance of active histone modifications and their writers during ZGA in teleost embryos. Our data propose that developmental genes and housekeeping genes are distinctively regulated during ZGA; CBP/P300 activity is required for developmental gene activation, whereas housekeeping genes depend on non-CBP/P300 histone acetylations H3K9ac/H4K16ac/H3K14ac. Moreover, accumulation of H3K4me2/3 is not prerequisite for activation of all types of genes during ZGA, in contrast to previous reports with cell lines. Finally, temporal accumulation of H3.3S31ph greatly enhances CBP/P300 activity specifically at ZGA, ensuring the activation of developmental genes. Our data demonstrate that multiple histone modifications cooperatively shape ZGA-specific gene activation programs in non-mammalian vertebrates.
    DOI:  https://doi.org/10.1038/s41467-025-60246-x
  4. Cell Rep. 2025 Jun 13. pii: S2211-1247(25)00627-8. [Epub ahead of print]44(6): 115856
    Cohesin supercoils DNA during loop extrusion.
    Iain F Davidson, Roman Barth, Kota Nagasaka, Wen Tang, Gordana Wutz, Sabrina Horn, Richard Janissen, Roman R Stocsits, Emilia Chlosta, Benedikt W Bauer, Cees Dekker, Jan-Michael Peters.
      Cohesin extrudes genomic DNA into loops that promote chromatin assembly, gene regulation, and gene recombination. Loop extrusion depends on large-scale conformational changes in cohesin, but how these translocate DNA is poorly understood. Here, we provide evidence that cohesin negatively supercoils DNA during loop extrusion. Supercoiling requires the engagement of cohesin's ATPase heads, DNA clamping by these heads, and a DNA-binding site on cohesin's hinge, indicating that cohesin twists DNA when constraining it between the hinge and the clamp. A cohesin mutant defective in negative supercoiling forms shorter loops in cells, and a similar, although weaker, phenotype is observed after the depletion of topoisomerase I. These results suggest that supercoiling is an integral part of the loop-extrusion mechanism and that relaxation of supercoiled DNA is required for cohesin-mediated loop extrusion and genome architecture.
    Keywords:  CP: Molecular biology; SMC complexes; cohesin; loop extrusion; supercoiling; topoisomerases
    DOI:  https://doi.org/10.1016/j.celrep.2025.115856
  5. Biochem J. 2025 Jun 17. pii: BCJ20253037. [Epub ahead of print]
    Multiple transactivation domains of EZH2 bind to the TAZ2 domain of p300 and stimulate acetyltransferase function of p300.
    Dustin Becht, Soumi Biswas, Chenxi Xu, Hongwen Xuan, Moustafa Khalil, Ling Cai, Catherine Musselman, Xin Liu, El Bachir Affar, Xiaobing Shi, Gang Wang, Tatiana Kutateladze.
      The H3K27me-specific methyltransferase EZH2 is the catalytic subunit of the repressive complex PRC2. EZH2 is typically implicated in transcriptional silencing but can also activate gene expression. Here, we show that EZH2 contains three adjacent transactivation domains (EZH2TAD) that are recognized by the TAZ2 domain of the transcriptional coactivator and acetyltransferase p300 (p300TAZ2). Binding interfaces identified by chemical shift perturbations in NMR experiments, measurements of binding affinities, and analysis of the complex formation by mass photometry demonstrate that each EZH2TAD can be concomitantly bound by a separate p300TAZ2. Interaction of EZH2TADs with p300TAZ2 stimulates H3K18- and H3K27-specific acetyltransferase activity of p300. We show that in 22Rv1 prostate cancer cells EZH2 occupies a large set of gene loci lacking H3K27me3, and these non-canonical genomic sites are instead co-occupied by p300, RNA Pol II and BRD4, and are rich in histone marks associated with transcriptional activation. Our findings shed light on the potential basis for such a high degree genetic co-localization through the direct association of p300TAZ2 with EZH2TADs.
    Keywords:  EZH2; TAZ2; chromatin; p300; transactivation domain
    DOI:  https://doi.org/10.1042/BCJ20253037
  6. Cell. 2025 Jun 12. pii: S0092-8674(25)00561-6. [Epub ahead of print]
    Bivalent chromatin instructs lineage specification during hematopoiesis.
    Masaki Yagi, Gracia Bonilla, Michael S Hoetker, Nikolaos Tsopoulidis, Joy E Horng, Chuck Haggerty, Alexander Meissner, Ruslan I Sadreyev, Hanno Hock, Konrad Hochedlinger.
      Developmental gene expression is regulated by the dynamic interplay of histone H3 lysine 4 (H3K4) and histone H3 lysine 27 (H3K27) methylation, yet the physiological roles of these epigenetic modifications remain incompletely understood. Here, we show that mice depleted for all forms of H3K4 methylation, using a dominant histone H3-lysine-4-to-methionine (H3K4M) mutation, succumb to a severe loss of all major blood cell types. H3K4M-expressing hematopoietic stem cells (HSCs) and committed progenitors are present at normal numbers, indicating that H3K4 methylation is dispensable for HSC maintenance and commitment but essential for progenitor cell maturation. Mechanistically, we reveal that H3K4 methylation opposes the deposition of repressive H3K27 methylation at differentiation-associated genes enriched for a bivalent (i.e., H3K4/H3K27-methylated) chromatin state in HSCs and progenitors. Indeed, by concomitantly suppressing H3K27 methylation in H3K4-methylation-depleted mice, we rescue the acute lethality, hematopoietic failure, and gene dysregulation. Our results provide functional evidence for the interaction between two crucial chromatin marks in mammalian tissue homeostasis.
    Keywords:  H3K27 methylation; H3K27M; H3K4 methylation; H3K4M; bivalent genes; differentiation; hematopoiesis; hematopoietic stem and progenitor cells; histone methylation; lysine-to-methionine mutation
    DOI:  https://doi.org/10.1016/j.cell.2025.05.011
  7. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00464-2. [Epub ahead of print]85(12): 2390-2408.e6
    SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
    Khoa A Tran, Michael Gilbert, Berta N Vazquez, Alessandro Ianni, Benjamin A Garcia, Alejandro Vaquero, Shelley L Berger.
      Sirtuin enzymes are deeply associated with senescence and aging. Sirtuin proteins are tightly regulated, but how their levels are governed during aging and how they elicit tissue-specific cellular changes are unclear. Here, we demonstrate that SIRT7 undergoes proteasomal degradation during senescence via targeting by the E3 ligase TRIP12. We identified the transcription factor nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) as an interactor of SIRT7 and found NUCKS1 recruitment onto chromatin during senescence mediated by SIRT7 loss, correlating with increased NUCKS1 acetylation. NUCKS1 depletion delayed senescence, leading to reduced inflammatory gene expression associated with transcription factors RELA and CEBPβ. In Sirt7 knockout and aged mouse livers, NUCKS1 was bound at the promoters and enhancers of age-related genes, and these regulatory regions gained accessibility during aging. Overall, our results uncover NUCKS1 as an interactor of SIRT7 and indicate that proteasomal loss of SIRT7 during senescence and liver aging promotes NUCKS1 acetylation and chromatin binding to induce metabolic and inflammatory genes.
    Keywords:  NUCKS1; SIRT7; acetylation; aging; post-translation modification; protein regulation; senescence; sirtuins
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.025
  8. Genome Biol. 2025 Jun 20. 26(1): 175
    Loop Catalog: a comprehensive HiChIP database of human and mouse samples.
    Joaquin Reyna, Kyra Fetter, Romeo Ignacio, Cemil Can Ali Marandi, Astoria Ma, Nikhil Rao, Zichen Jiang, Daniela Salgado Figueroa, Sourya Bhattacharyya, Ferhat Ay.
      HiChIP enables cost-effective and high-resolution profiling of chromatin loops. To leverage the increasing number of HiChIP datasets, we develop Loop Catalog ( https://loopcatalog.lji.org ), a web-based database featuring loop calls from over 1000 distinct human and mouse HiChIP samples from 152 studies plus 44 high-resolution Hi-C samples. We demonstrate its utility for interpreting GWAS and eQTL variants through SNP-to-gene linking, identifying enriched sequence motifs and motif pairs, and generating regulatory networks and 2D representations of chromatin structure. Our catalog spans more than 4.19M unique loops, and with embedded analysis modules, constitutes an important resource for the field.
    Keywords:  Chromatin loops; Database; GWAS; HiChIP; SNP-to-gene linking
    DOI:  https://doi.org/10.1186/s13059-025-03615-5
  9. Nat Commun. 2025 Jun 18. 16(1): 5340
    Divergence in a eukaryotic transcription factor's co-TF dependence involves multiple intrinsically disordered regions.
    Lindsey F Snyder, Emily M O'Brien, Jia Zhao, Jinye Liang, Baylee J Bruce, Yuning Zhang, Wei Zhu, Thomas H Cassier, Nicholas J Schnicker, Xu Zhou, Raluca Gordân, Bin Z He.
      Combinatorial control by transcription factors (TFs) is central to eukaryotic gene regulation, yet its mechanism, evolution, and regulatory impact are not well understood. Here we use natural variation in the yeast phosphate starvation (PHO) response to examine the genetic basis and species variation in TF interdependence. In Saccharomyces cerevisiae, the main TF Pho4 relies on the co-TF Pho2 to regulate ~28 genes, whereas in the related pathogen Candida glabrata, Pho4 has reduced Pho2 dependence and regulates ~70 genes. We found C. glabrata Pho4 (CgPho4) binds the same motif with 3-4 fold higher affinity. Machine learning and yeast one-hybrid assay identify two intrinsically disordered regions (IDRs) in CgPho4 that boost its activation domain's activity. In ScPho4, an IDR next to the DNA binding domain both allows for enhanced activity with Pho2 and inhibits activity without Pho2. This study reveals how IDR divergence drives TF interdependence evolution by influencing activation potential and autoinhibition.
    DOI:  https://doi.org/10.1038/s41467-025-59244-w
  10. Mol Cell. 2025 May 27. pii: S1097-2765(25)00309-0. [Epub ahead of print]
    CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance.
    Andreas Ingham, Ignacio Alonso de Vega, Louise Morlot, William Gittens, Ivo A Hendriks, Ellen S Kakulidis, Raimundo Freire, Norman E Davey, Julien P Duxin, Michael Lund Nielsen, Niels Mailand.
      Topoisomerase II (TOP2) inhibitors (TOP2i) are mainstay chemotherapeutic agents that undermine genome integrity by stabilizing TOP2-DNA complexes accompanied by DNA damage formation. Here, we reveal the uncharacterized protein CRAMP1 and H1 linker histones as key effectors of TOP2i tolerance in human cells. We demonstrate that CRAMP1 defines a dedicated histone H1 biogenesis factor stimulating transcription of both replicative and non-replicative H1 genes, driven by its concurrent targeting to histone gene loci and H1-specific promoter motifs. CRAMP1 promotes TOP2i tolerance by maintaining H1 supply, involving a novel mechanism uncoupled from TOP2i-induced DNA damage whereby reducing the H1 pool triggers unscheduled TOP2 substrate formation in low-accessibility chromatin states. This amplifies total demand for TOP2 activity, lowering the threshold for TOP2i-mediated exhaustion of TOP2. Our discoveries elucidate the mechanistic basis of histone H1 biogenesis in human cells, opening opportunities for selectively manipulating linker but not core histone supply and targeting cancer-associated H1 deficiency.
    Keywords:  chromatin; genome maintenance; histone H1; histone biogenesis; histone locus bodies; histone transcription; topoisomerase II; topoisomerase II inhibitors
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.006
  11. Phys Rev E. 2025 May;111(5-1): 054402
    Dynamic kissing model for enhancer-promoter communication on the surface of transcriptional condensates.
    Qing Zhang, Hualin Shi, Zhihua Zhang.
      Enhancer-promoter (E-P) communication is essential for gene transcription regulation in eukaryotes. Transcriptional condensates, which may form via liquid-liquid phase separation, are thought to enable E-P interactions. However, the kinetic mechanism of condensate-mediated E-P contacts and their effect on gene expression are unclear. Here we use a polymer physics-based model to investigate E-P communication in different condensate configurations. We find that E-P interactions are most consistent with experimental data when they occur on the surface of spherical condensates. Based on this finding, we propose a gene expression regulation model in which enhancers and promoters dynamically "kiss" on the condensate surface. We also show that our model can account for the phenomenon of gene expression bursting, as observed by single-molecule tracking. Our model provides a simple yet powerful framework for understanding enhancer-mediated gene regulation.
    DOI:  https://doi.org/10.1103/PhysRevE.111.054402
  12. Nucleic Acids Res. 2025 Jun 20. pii: gkaf497. [Epub ahead of print]53(12):
    Switchable RNA motifs for dynamic transcriptional control of RNA condensates.
    Anli A Tang, Martin Vincent Gobry, Shiyi Li, Ebbe Sloth Andersen, Elisa Franco.
      RNA-driven phase separation is emerging as a promising approach for engineering biomolecular condensates with diverse functionalities. Condensates form thanks to weak yet specific RNA-RNA interactions established by design via complementary sequence domains. Here, we demonstrate how RNA condensates formed by star-shaped RNA motifs, or nanostars, can be dynamically controlled when the motifs include additional linear or branch-loop domains that facilitate access of regulatory RNA molecules to the nanostar interaction domains. We show that condensates dissolve in the presence of RNA "invaders" that occlude selected nanostar bonds and reduce the valency of the nanostars, preventing phase separation. We further demonstrate that the introduction of "anti-invader" strands, complementary to the invaders, makes it possible to restore condensate formation. An important aspect of our experiments is that we demonstrate these behaviors in one-pot reactions, where RNA nanostars, invaders, and anti-invaders are simultaneously transcribed in vitro using short DNA templates. Our results lay the groundwork for engineering RNA-based assemblies with tunable, reversible condensation, providing a promising toolkit for synthetic biology applications requiring responsive, self-organizing biomolecular materials.
    DOI:  https://doi.org/10.1093/nar/gkaf497
  13. Nat Struct Mol Biol. 2025 Jun 13.
    H2A.Z reinforces maternal H3K4me3 formation and is essential for meiotic progression in mouse oocytes.
    Hailiang Mei, Ryoya Hayashi, Chisayo Kozuka, Mami Kumon, Haruhiko Koseki, Azusa Inoue.
      Mammalian oocytes establish a unique landscape of histone modifications, some of which are inherited by early embryos. How histone variants shape the maternal histone landscape remains unknown. Here we map histone H2A variants in mouse fully grown oocytes (FGOs) and find that H2A.Z forms broad domains across intergenic regions, along non-canonical H3K4me3 (ncH3K4me3). During oocyte growth, H2A.Z progressively transitions from an active promoter-rich, canonical distribution to a non-canonical broad distribution (ncH2A.Z). Depletion of H2A.Z in oocytes partially impairs ncH3K4me3 formation and causes severe defects in meiotic progression, which resemble Mll2-knockout oocytes. Conversely, depletion of ncH3K4me3 by Mll2 knockout also causes a reduction of ncH2A.Z in FGOs. Thus, our study suggests that ncH2A.Z and ncH3K4me3 reinforce each other to form functional oocytes.
    DOI:  https://doi.org/10.1038/s41594-025-01573-x
  14. Cell Rep Med. 2025 Jun 06. pii: S2666-3791(25)00265-4. [Epub ahead of print] 102192
    Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer.
    Sarah Naomi Olsen, Bryn Anderson, Charlie Hatton, Zhengtao Chu, Christopher Simpkins, Yanhe Wen, Wallace Bourgeois, Elena L Haarer, Myles Brown, Rinath Jeselsohn, Alana L Welm, Eneda Toska, Scott A Armstrong.
      KAT6A is a histone acetyltransferase that is emerging as a therapeutic target in cancer, including estrogen receptor-positive (ER+) breast cancer. Here, we perform CRISPR screens to identify the chromatin adaptor Menin as a regulator of KAT6A/B inhibitor response. Co-treatment with KAT6A/B and Menin inhibitors has synergistic anti-proliferative effects in ER+, but not ER-, breast cancer lines. Our data reveal that KAT6A and Menin-KMT2A cooperatively regulate ER-driven gene expression via direct effects on ESR1 expression and co-localization at ER target genes. Combined KAT6A/B and Menin inhibition displaces KAT6A and Menin-KMT2A from promoters of ER-driven genes leading to selective RNA polymerase II chromatin loss at these loci. Importantly, combined KAT6A/B and Menin inhibition is effective in ER+ patient-derived xenograft models and in multiple models of endocrine resistance. KAT6A/B and Menin inhibitors are currently in clinical trials and have shown manageable toxicity profiles, underscoring the potential therapeutic relevance for ER+ breast cancer.
    Keywords:  ER; KAT6A; Menin; breast cancer; chromatin; estrogen receptor
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102192
  15. Nature. 2025 Jun 18.
    In vivo mapping of mutagenesis sensitivity of human enhancers.
    Michael Kosicki, Boyang Zhang, Vivian Hecht, Anusri Pampari, Laura E Cook, Neil Slaven, Jennifer A Akiyama, Ingrid Plajzer-Frick, Catherine S Novak, Momoe Kato, Stella Tran, Riana D Hunter, Kianna von Maydell, Sarah Barton, Erik Beckman, Yiwen Zhu, Diane E Dickel, Anshul Kundaje, Axel Visel, Len A Pennacchio.
      Distant-acting enhancers are central to human development1. However, our limited understanding of their functional sequence features prevents the interpretation of enhancer mutations in disease2. Here we determined the functional sensitivity to mutagenesis of human developmental enhancers in vivo. Focusing on seven enhancers that are active in the developing brain, heart, limb and face, we created over 1,700 transgenic mice for over 260 mutagenized enhancer alleles. Systematic mutation of 12-base-pair blocks collectively altered each sequence feature in each enhancer at least once. We show that 69% of all blocks are required for normal in vivo activity, with mutations more commonly resulting in loss (60%) than in gain (9%) of function. Using predictive modelling, we annotated critical nucleotides at the base-pair resolution. The vast majority of motifs predicted by these machine learning models (88%) coincided with changes in in vivo function, and the models showed considerable sensitivity, identifying 59% of all functional blocks. Taken together, our results reveal that human enhancers contain a high density of sequence features that are required for their normal in vivo function and provide a rich resource for further exploration of human enhancer logic.
    DOI:  https://doi.org/10.1038/s41586-025-09182-w
  16. Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00626-6. [Epub ahead of print]44(7): 115855
    Repeated duplications and losses shaped SMC complex evolution from archaeal ancestors to modern eukaryotes.
    Jolien J E van Hooff, Maximilian W D Raas, Eelco C Tromer, Laura Eme.
      Across life, structural maintenance of chromosomes (SMC) complexes organize chromosomes. While most prokaryotes have one, eukaryotes usually possess four (condensin I, condensin II, cohesin, and SMC5/6), shaping their considerably larger genomes. Although essential, SMC complexes differ among model eukaryotes, suggesting underexplored diversity. Here, we reconstruct eukaryotic SMC complex evolution, revealing that the last eukaryotic common ancestor (LECA) had all four complexes, supporting a sophisticated LECA. Subsequently, condensin II was lost at least 30 times, making it one of the most frequently lost eukaryotic machineries. Moreover, multiple SMC complex components are more ancient and widespread than previously appreciated. Tracing prokaryotic origins, we propose that the SMC complex was already duplicated in the Thaumarchaeota-Aigarchaeota-Crenarchaeota-Korarchaeota (TACK) and Asgard archaeal ancestor, suggesting sophisticated chromosome organization in eukaryotes' archaeal ancestor. Gene duplications further expanded the eukaryotic SMC complex inventory, highlighting their significance in establishing eukaryotic complexity. Altogether, our work suggests major shifts in genome organization throughout eukaryote history.
    Keywords:  CP: Genomics; CP: Molecular biology; LECA; SMC5/6; chromatin; chromosome organization; cohesin; condensin; eukaryogenesis; evolutionary cell biology; genome organization; structural maintenance of chromosomes
    DOI:  https://doi.org/10.1016/j.celrep.2025.115855
  17. J Biol Chem. 2025 Jun 12. pii: S0021-9258(25)02222-7. [Epub ahead of print] 110372
    Induction of the zinc finger transcription factor GATA2 promotes kidney inflammation-related gene expression.
    Jun Takai, Hinata Ueki, Satoshi Uemura.
      Kidney diseases pose a medical challenge worldwide. Excessive kidney inflammation plays a central role in disease progression. While the transcription factor GATA binding protein 2 (GATA2) is known to govern the hematopoietic system, emerging evidence suggests that it also promotes kidney inflammation. To date, the precise molecular mechanisms underlying GATA2-mediated kidney inflammation remain unclear. Here, we examined the transcriptional landscape, genome-wide GATA2 occupancy, and chromatin accessibility upon GATA2 induction in kidney cells. We generated an inducible GATA2 expression system using a renal tubular cell line and then performed RNA-seq, Assay for Transposase-Accessible Chromatin (ATAC)-seq, and Cleavage Under Targets and Tagmentation (CUT&Tag). We also conducted ATAC-seq using GATA2-expressing cell fractions sorted from mouse kidney tissues. These comprehensive analyses demonstrated that GATA2 directly up-regulates genes associated with kidney inflammation. In particular, GATA2 bound to crucial kidney inflammation-associated gene loci and increased chromatin accessibility at these regions, including colony-stimulating factor 1 (Csf1), C-X-C motif chemokine ligand 10 (Cxcl10), and vascular cell adhesion molecule-1 (Vcam1). Motif analysis revealed that the binding sequences of the activator protein-1 (AP-1), an inflammation-induced transcription factor, are frequently located adjacent to genomic regions where GATA2 increases chromatin accessibility. Furthermore, the up-regulation of Csf1, Cxcl10, and Vcam1 following GATA2 induction was attenuated by the AP-1-specific inhibitor T-5224. Overall, this study is the first to determine genome-wide GATA2 occupancy and its impact on chromatin accessibility in kidney cells. These findings provide molecular insights into the role of GATA2 in kidney inflammation.
    Keywords:  ATAC-seq; CUT&Tag; Csf1; Cxcl10; GATA transcription factor; GATA2; Vcam1; chromatin accessibility; inflammation; kidney
    DOI:  https://doi.org/10.1016/j.jbc.2025.110372
  18. New Phytol. 2025 Jun 19.
    Mechanisms driving functional divergence of transcription factor paralogs.
    Isabella J Higgins, Sarah G Choudury, Aman Y Husbands.
      Transcription factors (TFs) are core components of the regulatory toolkits that control gene expression. The sophistication of these regulatory toolkits dramatically increased during Eukaryotic evolution, accomplished in part by the duplication of existing TFs and the subsequent repurposing of these new paralogs. This process, termed functional divergence, drove the evolution of increasingly elaborate programs of gene expression and, in turn, cellular and organismal complexity. Mechanisms generating functional divergence of TF paralogs are thus of significant interest. Here, we review the numerous mechanisms that can lead to divergence of TF paralogs, drawing on studies from across Eukaryota but with a special emphasis on the plant kingdom. We end by placing these mechanisms back into a broader evolutionary context.
    Keywords:  DNA‐binding affinity; antifunctionalization; cooperativity; evolution; functional divergence; paralogs; shared binding sites; transcription factors
    DOI:  https://doi.org/10.1111/nph.70309
  19. iScience. 2025 Jun 20. 28(6): 112717
    Histone deacetylation as a landmark for Sgo2 relocation from centromeres to subtelomeres during interphase.
    Miho Osaki, Yoko Otsubo, Atika Nurani, Nanoka Asano, Kota Ono, Junko Kanoh.
      Shugoshin family proteins localize to centromeres and play pivotal roles in chromosome segregation during mitosis and meiosis. In fission yeast, the Shugoshin paralog Sgo2 relocates from centromeres to subtelomeres during interphase, where it contributes to gene repression by establishing a subtelomere-specific condensed chromatin structure known as the knob. However, the mechanisms underlying subtelomere-specific Sgo2 localization and knob formation during interphase remain poorly understood. Here, we identified Nts1, a component of the histone deacetylase complex, as a key regulator of Sgo2 localization through a genetic screen. Deletion of both nts1 + and set2 + (which encodes a histone H3-K36 methyltransferase) resulted in an almost complete loss of Sgo2 localization and knob formation at subtelomeres, indicating that Nts1 and Set2 function redundantly to target Sgo2 to subtelomeres. Notably, Nts1 localizes to subtelomeres during interphase and promotes histone H4 deacetylation, suggesting that histone deacetylation serves as a landmark for subtelomere-specific Sgo2 localization and knob formation.
    Keywords:  Chromosome organization; Molecular Genetics; Molecular interaction; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2025.112717
  20. Plant Cell. 2025 Jun 14. pii: koaf148. [Epub ahead of print]
    Polycomb Repressive Complex 2 facilitates the transition from heterotrophy to photoautotrophy during seedling emergence.
    Naseem Samo, María Guadalupe Trejo-Arellano, Lenka Gahurová, Alexander Erban, Alina Ebert, Quentin Rivière, Jiří Kubásek, Fatemeh Aflaki, Helena Hönig Mondeková, Armin Schlereth, Annick Dubois, Mingxi Zhou, Ondřej Novák, Jiří Šantrůček, Daniel Bouyer, Francois Roudier, Joachim Kopka, Iva Mozgová.
      The seed-to-seedling transition represents a key developmental and metabolic switch in plants. Catabolism of seed storage reserves fuels germination and early seedling emergence until photosynthesis is established. The seed-to-seedling developmental transition is controlled by Polycomb repressive complex 2 (PRC2). However, the coordination of PRC2 activity and its contribution to transcriptional reprogramming during seedling establishment remain unknown. By analyzing H3K27me3 re-distribution and changes in gene transcription in the shoot and root tissues of heterotrophic and photoautotrophic Arabidopsis (Arabidopsis thaliana) seedlings, we reveal two phases of PRC2-mediated gene repression. The first phase is independent of light and photosynthesis and results in the irreversible repression of the embryo maturation program, marked by heterotrophy and reserve storage molecule biosynthesis. The second phase is associated with the repression of metabolic pathways related to germination and early seedling emergence, and H3K27me3 deposition in this phase is sensitive to photosynthesis inhibition. We show that preventing the transcription of the PRC2-repressed glyoxylate cycle gene ISOCITRATE LYASE promotes the vegetative phase transition in PRC2-depleted plants. Our findings underscore a key role of PRC2-mediated transcriptional repression in the coordinated metabolic and developmental switches that occur during seedling emergence and emphasizes the close connection between metabolic and developmental identities.
    Keywords:  Arabidopsis; Polycomb repressive complex 2; heterotrophy; photoautotrophy; seed-to-seedling
    DOI:  https://doi.org/10.1093/plcell/koaf148
  21. Cancer Discov. 2025 Jun 19.
    KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.
    Nicole L Michmerhuizen, Emily B Heikamp, Ilaria Iacobucci, Masayuki Umeda, Bright Arthur, Vibhor Mishra, Chun Shik Park, Danika Di Giacomo, Ryan Hiltenbrand, Qingsong Gao, Sandi Radko-Juettner, Josi Lott, Cynthia Martucci, Varsha Subramanyam, Charlie Hatton, Daniela V Wenge, Pradyuamna Baviskar, Pablo Portola, Aurelie Claquin, Bappaditya Chandra, David W Baggett, Ali Khalighifar, Hongling Huang, Peipei Zhou, Lingyun Long, Hao Shi, Yu Sun, Evangelia K Papachristou, Chandra Sekhar Reddy Chilamakuri, Francisca N de Luna Vitorino, Joanna M Gongora, Huiyun Wu, Stanley B Pounds, Laura J Janke, Alex Kentsis, Clive S D'Santos, Benjamin A Garcia, Richard W Kriwacki, Hongbo Chi, Jeffery M Klco, Scott A Armstrong, Charles G Mullighan.
      NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML). NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Kat6a and Kat7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1772
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