bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–06–08
24 papers selected by
Connor Rogerson, University of Cambridge
  1. p53 reveals principles of chromatin remodeling and enhancer activation.
  2. Pioneering new enhancers by GATA3: role of facilitating transcription factors and chromatin remodeling.
  3. Eomesodermin in conjunction with the BAF complex promotes expansion and invasion of the trophectoderm lineage.
  4. Widespread impact of nucleosome remodelers on transcription at cis-regulatory elements.
  5. DNA G-quadruplex structures act as functional elements in α- and β-globin enhancers.
  6. The HP1 box of KAP1 organizes HP1α for silencing of endogenous retroviral elements in embryonic stem cells.
  7. Distinct proliferative and neuronal programmes of chromatin binding and gene activation by ASCL1 are cell cycle stage-specific.
  8. Iterative deep learning design of human enhancers exploits condensed sequence grammar to achieve cell-type specificity.
  9. SPT6 regulates H3K14Ac deposition in mouse embryonic stem cells.
  10. Jund orchestrates cis-regulatory element dynamics to facilitate endothelial-to-hematopoietic transition.
  11. Sunflower seed-specific HSFA9 induces persistent chromatin accessibility during seed-to-seedling developmental transition.
  12. Subnucleosome preference of human chromatin remodeller SMARCAD1.
  13. Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers.
  14. A role for pH dynamics regulating transcription factor DNA-binding selectivity.
  15. Integrating gene expression, genomic, and phosphoproteomic data to infer transcription factor activity in lung cancer.
  16. The pioneer transcription factor Zelda controls the exit from regeneration and restoration of patterning in Drosophila.
  17. SWI/SNF ATPase silenced HLF potentiates lung metastasis in solid cancers.
  18. Compromised two-start zigzag chromatin folding in immature mouse retina cells driven by irregularly spaced nucleosomes with short DNA linkers.
  19. H3.3 deposition counteracts the replication-dependent enrichment of H3.1 at chromocenters in embryonic stem cells.
  20. PROX1 is an early driver of lineage plasticity in prostate cancer.
  21. Androgen receptor-mediated assisted loading of the glucocorticoid receptor modulates transcriptional responses in prostate cancer cells.
  22. Enhancer RNA-mediated transcriptional regulatory programs reveal the malignant progression of glioma.
  23. Direct detection of 8-oxo-dG using nanopore sequencing.
  24. HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism.
  1. Nucleic Acids Res. 2025 Jun 06. pii: gkaf465. [Epub ahead of print]53(11):
    p53 reveals principles of chromatin remodeling and enhancer activation.
    Martin Fischer, Robert Schwarz, Konstantin Riege, Silke Förste, Katjana Schwab, Elina Wiechens, Alena van Bömmel, Steve Hoffmann.
      Pioneer transcription factors can bind to closed chromatin, initiating its opening and subsequent gene activation. However, the specific features that enable transcription factors to activate particular loci remain largely undefined. Here, we show that the transcription factor p53 unexpectedly initiates epigenetic remodeling at the majority of its binding sites and drives transcription at select loci. Our quantitative epigenetic data reveal that p53 establishes new enhancers, while quantitative transcription initiation analyses indicate that high local p53 abundance and sequence-specific binding are key features of sites where p53 successfully induces transcription. Surprisingly, we observed a spatial overlap between p53 binding sites and transcription initiation sites, suggesting a decoupling of these two events. Our results reveal that p53 activity unfolds across three distinct layers: histone modification, nucleosome eviction, and transcription initiation, with the latter driven by dynamic rather than static p53 DNA binding. These insights expand our understanding of the function of p53 by showing it not only actively initiates transcription but also broadly remodels chromatin. Overall, these findings offer a conceptual framework to explore how transcription factors regulate chromatin states and gene expression.
    DOI:  https://doi.org/10.1093/nar/gkaf465
  2. Nucleic Acids Res. 2025 Jun 06. pii: gkaf473. [Epub ahead of print]53(11):
    Pioneering new enhancers by GATA3: role of facilitating transcription factors and chromatin remodeling.
    Krystal A Orlando, Sara A Grimm, Paul A Wade.
      Pioneer transcription factors (PTFs) bind to inaccessible chromatin and recruit collaborating transcription factors to promote chromatin accessibility. However, mechanisms driving PTFs to specify collaborating transcription factor recruitment and chromatin remodeling remain unclear. Here, we utilize inducible expression of a PTF, GATA3, in a basal breast cancer cell line (SUM159PT) to mechanistically address the collaborating transcription factor requirements and the local chromatin architecture delineating GATA3-depenent chromatin accessibility and enhancer formation (productive sites) versus GATA3-bound inaccessible chromatin (unproductive sites). Transcription factor footprinting in productive sites illustrated enrichment of GATA3 with AP-1 transcription factor. Together, GATA3 and AP-1 colocalize at primed enhancers with p300 and BRG1 where nucleosome positioning is influenced by GATA3 binding. Although inhibition of AP-1 binding affects a small subset of productive sites, we demonstrate that inhibition of SWI/SNF ATPases results in dramatic loss of GATA3-dependent chromatin accessibility, binding, and alterations in local chromatin architecture. We conclude that GATA3-dependent gains in chromatin accessibility require chromatin remodeling and that accessibility at some loci is facilitated by collaborating transcription factors like AP-1.
    DOI:  https://doi.org/10.1093/nar/gkaf473
  3. Nat Commun. 2025 May 31. 16(1): 5079
    Eomesodermin in conjunction with the BAF complex promotes expansion and invasion of the trophectoderm lineage.
    Alexandra Maria Bisia, Maria-Eleni Xypolita, Elizabeth K Bikoff, Elizabeth J Robertson, Ita Costello.
      The T-box transcription factor (TF) Eomesodermin/Tbr2 (Eomes) is essential for maintenance of the trophectoderm (TE) lineage, but the molecular mechanisms underlying this critical role remain obscure. Here, we show in trophoblast stem cells (TSCs) that Eomes partners with several TE-specific TFs as well as chromatin remodellers, including Brg1 and other subunits of the BAF complex. Degron-mediated Eomes protein depletion results in genome-wide loss of chromatin accessibility at TSC-specific loci. These overlap with a subset of sites that lose accessibility following Brg1 inhibition, suggesting that Eomes acts as a "doorstop" controlling TSC chromatin accessibility. Eomes depletion also causes transcriptional misregulation of TSC maintenance and early differentiation markers. An additional subset of Eomes-dependent genes encode intercellular/matricellular interaction and cytoskeletal components, likely explaining the implantation defects of Eomes-null embryos. Thus, Eomes promotes TE lineage maintenance by sustaining trophectoderm-specific chromatin accessibility, while promoting the gene regulatory networks that modulate expansion and cell behaviour during implantation.
    DOI:  https://doi.org/10.1038/s41467-025-60417-w
  4. Cell Rep. 2025 May 30. pii: S2211-1247(25)00538-8. [Epub ahead of print]44(6): 115767
    Widespread impact of nucleosome remodelers on transcription at cis-regulatory elements.
    Benjamin J Patty, Rinku Dhungana, Sarah J Hainer.
      Nucleosome remodelers and regulatory factors collaborate to establish chromatin environments that control gene expression through cis-regulatory elements (CREs) such as promoters and enhancers, which drive transcription of mRNAs and CRE-associated non-coding RNAs (ncRNAs). Two CRE-associated ncRNAs include upstream antisense RNAs (uaRNAs) and enhancer RNAs (eRNAs). The role of remodelers in regulating CRE activity remains incompletely understood. Here, we investigated how SNF2-family remodelers regulate mRNA, eRNA, and uaRNA transcription in murine embryonic stem cells. We identified thousands of misregulated transcripts upon remodeler depletion and defined contributions of understudied remodelers. We find that paired mRNAs and eRNAs are co-regulated, while mRNAs and uaRNAs sharing a promoter are independently regulated by remodelers. Mechanistic studies reveal that CHD8 and SRCAP modulate transcription through canonical transcription factor and histone variant mechanisms, while other remodelers, including SMARCAL1, impact transcription indirectly by maintaining genomic stability. Our findings define classes of SNF2 remodelers in regulating the CRE-associated transcriptome.
    Keywords:  CHD8; CP: Molecular biology; SMARCAL1; SRCAP; chromatin; eRNA; embryonic stem cells; nucleosome; remodelers; transcriptomics; uaRNA
    DOI:  https://doi.org/10.1016/j.celrep.2025.115767
  5. Genome Biol. 2025 Jun 04. 26(1): 155
    DNA G-quadruplex structures act as functional elements in α- and β-globin enhancers.
    Colm Doyle, Krzysztof Herka, Sean M Flynn, Larry Melidis, Somdutta Dhir, Stefan Schoenfelder, David Tannahill, Shankar Balasubramanian.
       BACKGROUND: Enhancer elements interact with target genes at a distance to modulate their expression, but the molecular details of enhancer-promoter interaction are incompletely understood. G-quadruplex DNA secondary structures (G4s) have recently been shown to co-occur with 3D chromatin interactions; however, the functional importance of G4s within enhancers remains unclear.
    RESULTS: In this study, we identify novel G4 structures within two locus control regions at the human α- and β-globin loci. We find that mutating G4 motifs by genome editing prevents their folding into G4 structures in cells and disrupts 3D enhancer-promoter interactions and target gene expression in a manner comparable to whole enhancer deletion. Furthermore, restoration of G4 structure formation using a dissimilar G4-forming primary sequence recovers specific enhancer-gene interactions and gene expression. Through proteomic, biophysical, and genomic profiling, we find that enhancer G4s are tightly linked to the maintenance of an active chromatin state and RNA polymerase II recruitment to regulate target gene expression.
    CONCLUSIONS: Our study shows that folded G4 structures can act as functional elements that mediate 3D enhancer-promoter interactions to support enhancer-driven globin gene regulation.
    Keywords:  3D chromatin interactions; Enhancers; Epigenetics; G-quadruplex structures
    DOI:  https://doi.org/10.1186/s13059-025-03627-1
  6. Nat Commun. 2025 May 31. 16(1): 5066
    The HP1 box of KAP1 organizes HP1α for silencing of endogenous retroviral elements in embryonic stem cells.
    Nitika Gaurav, Ryan O'Hara, Usman Hyder, Weihua Qin, Cheenou Her, Hector Romero, Amarjeet Kumar, Maria J Marcaida, Rohit K Singh, Ruud Hovius, Karthik Selvam, Jiuyang Liu, Sara Martire, Yuhang Yao, Ashwini Challa, Matteo Dal Peraro, Beat Fierz, Hidetoshi Kono, M Cristina Cardoso, Galia T Debelouchina, Heinrich Leonhardt, Iván D'Orso, Laura A Banaszynski, Tatiana G Kutateladze.
      Repression of endogenous retroviral elements (ERVs) is facilitated by KAP1 (KRAB-associated protein 1)-containing complexes, however the underlying mechanism remains unclear. Here, we show that binding of KAP1 to the major component of the heterochromatin spreading and maintenance network, HP1α, plays a critical role in silencing of repetitive elements. Structural, biochemical and mutagenesis studies demonstrate that the association of the HP1 box of KAP1 (KAP1Hbox) with the chromoshadow domain of HP1α (HP1αCSD) leads to a symmetrical arrangement of HP1αCSD and multimerization that may promote the closed state of chromatin. The formation of the KAP1Hbox-HP1αCSD complex enhances charge driven DNA binding and phase separation activities of HP1α. ChIP-seq and ATAC-seq analyses using KAP1 knock out mouse embryonic stem cells expressing wild type KAP1 or HP1-deficient KAP1 mutant show that in vivo, KAP1 engagement with HP1 is required for maintaining inaccessible chromatin at ERVs. Our findings provide mechanistic and functional insights that further our understanding of how ERVs are silenced.
    DOI:  https://doi.org/10.1038/s41467-025-60279-2
  7. Development. 2025 Jun 02. pii: dev.204816. [Epub ahead of print]
    Distinct proliferative and neuronal programmes of chromatin binding and gene activation by ASCL1 are cell cycle stage-specific.
    William F Beckman, Lydia M Parkinson, Lewis Chaytor, Anna Philpott.
      ASCL1 is a potent proneural factor with paradoxical functions during development, promoting both progenitor pool expansion and neuronal differentiation. How a single factor executes and switches between these potentially opposing functions remain to be understood. Using neuroblastoma cells as a model system, we show that ASCL1 exhibits cell cycle phase-dependent chromatin binding patterns. In cycling cells, S/G2/M phase-enriched binding occurs at promoters of transcribed pro-mitotic genes, while G1 phase-enriched binding of ASCL1 is associated with the priming of pro-neuronal enhancer loci. Prolonged G1 arrest is further required to activate these ASCL1-bound and primed neuronal enhancers to drive neuronal differentiation. Thus, we reveal that the same transcription factor can control distinct transcriptional programmes at different cell cycle stages, and demonstrate how lengthening of G1 allows engagement of a differentiation programme by turning unproductive factor binding into productive interactions.
    Keywords:  ASCL1; Cell cycle; Differentiation; Neuroblastoma
    DOI:  https://doi.org/10.1242/dev.204816
  8. Cell Syst. 2025 May 30. pii: S2405-4712(25)00135-8. [Epub ahead of print] 101302
    Iterative deep learning design of human enhancers exploits condensed sequence grammar to achieve cell-type specificity.
    Christopher Yin, Sebastian Castillo-Hair, Gun Woo Byeon, Peter Bromley, Wouter Meuleman, Georg Seelig.
      An important and largely unsolved problem in synthetic biology is how to target gene expression to specific cell types. Here, we apply iterative deep learning to design synthetic enhancers with strong differential activity between two human cell lines. We initially train models on published datasets of enhancer activity and chromatin accessibility and use them to guide the design of synthetic enhancers that maximize predicted specificity. We experimentally validate these sequences, use the measurements to re-optimize the model, and design a second generation of enhancers with improved specificity. Our design methods embed relevant transcription factor binding site (TFBS) motifs with higher frequency than comparable endogenous enhancers while using a more selective motif vocabulary, and we show that enhancer activity is correlated with transcription factor expression at the single-cell level. Finally, we characterize causal features of top enhancers via perturbation experiments and show that enhancers as short as 50 bp can maintain specificity. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  cell-type specificity; chromatin accessibility; cis-regulatory; deep learning; enhancer; enhancer design; generative design; synthetic biology; synthetic enhancers
    DOI:  https://doi.org/10.1016/j.cels.2025.101302
  9. Cell Rep. 2025 May 30. pii: S2211-1247(25)00528-5. [Epub ahead of print]44(6): 115757
    SPT6 regulates H3K14Ac deposition in mouse embryonic stem cells.
    Daixuan Zhang, Li Dong, Ying Cai, Peng Zhao, Qingqing Cai, Jian Zhang, Yajun Hu, Mandi Mu, Siyi Cheng, Jin Wang, Min Zeng, Chenxi He, Lei Zhang, Hui Yang, Fei Xavier Chen, Li Tan, Feizhen Wu, Yujiang Geno Shi, Wenqi Xu, Hongjie Shen.
      SPT6 (suppressor of Ty 6) is a conserved histone chaperone that plays critical roles in RNA Pol II progression and nucleosome reassembly. However, the functions of SPT6 in chromatin regulation remain incompletely understood. Here, we show that SPT6 localizes to histone H3 lysine 14 acetylation (H3K14Ac)-enriched regions in mouse embryonic stem cells (mESCs). Loss of SPT6 leads to reduced H3K14Ac levels and diminished transcription. Mechanistically, we show that SPT6 enhances the chromatin binding of the acetyltransferases KAT7 and KAT6A/KAT6B, which are responsible for H3K14Ac deposition, but SPT6-facilitated H3K14Ac can also occur in a KAT7/6A/6B independent manner. Our findings highlight a vital role for SPT6 in preserving the H3K14Ac landscape in mESCs, providing new insights into the crosstalk between transcription machinery and H3K14Ac regulation in mammals.
    Keywords:  CP: Stem cell research; H3K14Ac; SPT6; epigenetics; histone modification; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2025.115757
  10. Proc Natl Acad Sci U S A. 2025 Jun 10. 122(23): e2426714122
    Jund orchestrates cis-regulatory element dynamics to facilitate endothelial-to-hematopoietic transition.
    Jiani Guo, Mengyao Liu, Feng Liu, Lu Wang.
      The tightly controlled spatiotemporal expression of developmental genes depends on the concerted action of cis-regulatory elements (CREs) and transcription factors (TFs) to ensure cell fate decisions. Endothelial-to-hematopoietic transition (EHT) is a cell fate transition process by which endothelial cells acquire hematopoietic identity and become hemogenic endothelial cells (HECs) and then hematopoietic stem and progenitor cells, but the underlying CRE network dynamics and its regulation by TFs remain unclear. In this study, we characterized the dynamics of CRE activation and TF occupancy during zebrafish EHT, and found that the enhancer-promoter collaboration forms the basis for EHT. Moreover, a ubiquitously expressed TF AP-1 collaborates with diverse lineage-specific TFs to remodel enhancer landscape. Deletion of AP-1 family member Jund impaired hematopoietic specification, resulting from the enhanced endothelial identity in the HEC. Mechanistically, Jund and hematopoietic TF Hoxa9a collectively repress the activity of an endothelial-related dll4 enhancer through tight control of the active histone modification H3K27ac. Our study provides insights into the cooperative function among ubiquitous TFs and cell type-specific TFs in orchestrating cell fate transition.
    Keywords:  AP-1; Jund; cis-regulatory elements; endothelial-to-hematopoietic transition; hematopoietic stem and progenitor cells
    DOI:  https://doi.org/10.1073/pnas.2426714122
  11. Plant J. 2025 Jun;122(5): e70261
    Sunflower seed-specific HSFA9 induces persistent chromatin accessibility during seed-to-seedling developmental transition.
    Pilar Prieto-Dapena, Raúl Carranco, Concepción Almoguera, Juan Jordano.
      HSFA9 (A9) is a seed-specific transcription factor that contributes to seed longevity in sunflower. A9 also links the regulation of seed maturation with that of early seedling greening through its effects on various light receptors. Transcriptomic analyses of transgenic tobacco seeds suggested that A9 might affect chromatin remodeling. Here, using formaldehyde-assisted isolation of regulatory elements (FAIRE) and micrococcal nuclease digestion, we analyzed the A9 effects on chromatin accessibility shortly after seed imbibition in the proximal promoter region of developmentally relevant genes, including HY5 and PHYA. A9, expressed from a seed-specific promoter, enhanced chromatin accessibility in the analyzed regions. Converse, promoter-specific, effects were observed upon loss-of-function of tobacco A9 (NtA9) in transgenic seeds. Furthermore, a memory effect was observed, as the induced chromatin accessibility persisted for up to 4 days after seed imbibition, when A9 was no longer detected. The A9-induced chromatin effects involved labile/unstable nucleosomes placed at proximal promoter locations where A9 induced substantial nucleosomal depletion. Specific inhibitors of BRAHMA-like ATPase subunits of SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin-remodeling complexes and histone deacetylase (HDAC) impaired A9-induced memory. Thus, SWI/SNF remodeling and HDAC activity mechanistically contribute to the A9-induced memory. Furthermore, SWI/SNF inhibition specifically reduced the HY5 and PHYA promoter accessibility in both transgenic and non-transgenic seeds. Our results identify HSFA9 as a potential master, short-term, 'epigenetic' regulator that operates in seeds in anticipation of seedling establishment. The new, A9-induced, somatic memory effect reported here may facilitate early seedling greening and stress tolerance during the seed-to-seedling developmental transition.
    Keywords:  HSFA9; Nicotiana tabacum; SWI/SNF remodeling; chromatin accessibility; seed‐to‐seedling transition; short‐term memory
    DOI:  https://doi.org/10.1111/tpj.70261
  12. Nature. 2025 Jun 04.
    Subnucleosome preference of human chromatin remodeller SMARCAD1.
    Pengjing Hu, Jingxi Sun, Hongyao Sun, Kangjing Chen, Youyang Sia, Xian Xia, Qiaoran Xi, Zhucheng Chen.
      Chromatin remodellers are pivotal in the regulation of nucleosome dynamics in cells, and they are important for chromatin packaging, transcription, replication and DNA repair1. Here we show that the human chromatin remodeller SMARCAD1 exhibits a substrate preference for subnucleosomal particles over the canonical nucleosome. Cryo-electron microscopy structures of SMARCAD1 bound to the nucleosome and hexasome provide mechanistic insights into the substrate selectivity. SMARCAD1 binds to the hexasome through multiple family-specific elements that are essential for the functions in vitro and in cells. The enzyme binds to the canonical nucleosome in an inactive conformation, which accounts for its diminished activity towards the nucleosome. Notably, the histone chaperone FACT complex acts synergistically with H2A-H2B to promote the activity of SMARCAD1 in nucleosome remodelling. Together, our findings reveal an avenue for chromatin regulation, whereby subnucleosomes are remodelled through an ATP-dependent process.
    DOI:  https://doi.org/10.1038/s41586-025-09100-0
  13. Blood. 2025 Jun 02. pii: blood.2024028128. [Epub ahead of print]
    Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers.
    Anna-Karina Felder, Sjoerd J D Tjalsma, Han J M P Verhagen, Rezin Majied, Marjon J A M Verstegen, Thijs C J Verheul, Jeffrey van Haren, Rebecca Mohnani, Richard Gremmen, Peter H L Krijger, Sjaak Philipsen, Emile van den Akker, Wouter de Laat.
      The human genome contains regulatory DNA elements, enhancers, that can activate gene transcription over long chromosomal distances. Here, we show that enhancer distance can be critical for gene silencing. We demonstrate that linear recruitment of the normally distal strong HBB enhancer to developmentally silenced embryonic HBE or fetal HBG promoters, through deletion or inversion of intervening DNA sequences, results in their strongly reactivated expression in adult erythroid cells and ex vivo differentiated hematopoietic stem and progenitor cells. A similar observation is made in the HBA locus, where deletion-to-recruit of the distal enhancer strongly reactivates embryonic HBZ expression. Overall, our work assigns function to seemingly non-regulatory genomic segments: by providing linear separation they may support genes to autonomously control their transcriptional response to distal enhancers.
    DOI:  https://doi.org/10.1182/blood.2024028128
  14. Nucleic Acids Res. 2025 May 22. pii: gkaf474. [Epub ahead of print]53(10):
    A role for pH dynamics regulating transcription factor DNA-binding selectivity.
    Kyle P Kisor, Diego Garrido Ruiz, Matthew P Jacobson, Diane L Barber.
      Intracellular pH (pHi) dynamics regulates diverse cell processes such as proliferation, dysplasia, and differentiation, often mediated by the protonation state of a functionally critical histidine residue in endogenous pH sensing proteins. How pHi dynamics can directly regulate gene expression or whether transcription factors can function as pH sensors has received limited attention. We tested the prediction that transcription factors with a histidine in their DNA-binding domain (DBD) that forms hydrogen bonds with nucleotides can have pH-regulated activity, which is relevant to more than 85 transcription factors in distinct families, including FOX, KLF, SOX, and MITF/Myc. Focusing on FOX family transcription factors, we use unbiased SELEX-seq to identify pH-dependent DNA-binding motif preferences and confirm pH-regulated binding affinities for FOXC2, FOXM1, and FOXN1 to a canonical FkhP DNA motif that are greater at pH 7.0 compared with pH 7.5 and for FOXN1 to a preferred FHL motif at higher pHi in cells. For FOXC2, we also find that greater activity for an FkhP motif at lower pH is dependent on a conserved histidine (His122) in the DBD. ChIP-seq and RNA-seq with FOXC2 also reveal pH-dependent differences in enriched promoter motifs. Our findings identify pH-regulated transcription factor-DNA binding selectivity with relevance to how pHi dynamics can regulate gene expression for myriad cell behaviours.
    DOI:  https://doi.org/10.1093/nar/gkaf474
  15. NAR Genom Bioinform. 2025 Jun;7(2): lqaf068
    Integrating gene expression, genomic, and phosphoproteomic data to infer transcription factor activity in lung cancer.
    Chiara Carrino, Gerardo Pepe, Luca Parca, Manuela Helmer-Citterich, Pier Federico Gherardini.
      Transcription factors (TFs) are key regulators of cellular gene expression programs in health and disease. Here we set out to integrate genomic, transcriptomic, and phosphoproteomic data to characterize TF activity in lung adenocarcinoma patients. Using expression data from patient samples and genomic information on TF binding to super-enhancers, starting from a list of 1667 human TFs we calculated a patient-specific activity score and identified 34 with perturbed activity in the cancer samples, as evidenced by the expression of their direct targets. We then leveraged phosphoproteomic data on the same samples to identify phosphorylation events that modulate TF activity. This novel data integration approach to TF characterization led to the identification of ERG as a key regulator in lung adenocarcinoma whose activity strongly correlates with patient survival.
    DOI:  https://doi.org/10.1093/nargab/lqaf068
  16. Sci Adv. 2025 Jun 06. 11(23): eads5743
    The pioneer transcription factor Zelda controls the exit from regeneration and restoration of patterning in Drosophila.
    Anish Bose, Keaton Schuster, Chandril Kodali, Surabhi Sonam, Rachel K Smith-Bolton.
      Many animals can regenerate tissues after injury. While the initiation of regeneration has been studied extensively, how the damage response ends and normal gene expression returns is unclear. We found that in Drosophila wing imaginal discs, the pioneer transcription factor Zelda controls the exit from regeneration and return to normal gene expression. Optogenetic inactivation of Zelda during regeneration disrupted patterning, induced cell fate errors, and caused morphological defects yet had no effect on normal wing development. Using Cleavage Under Targets & Release Using Nuclease, we identified targets of Zelda important for the end of regeneration, including genes that control wing margin and vein specification, compartment identity, and cell adhesion. We also found that GAGA factor and Fork head similarly coordinate patterning after regeneration and that chromatin regions bound by Zelda increase in accessibility during regeneration. Thus, Zelda orchestrates the transition from regeneration to normal gene expression, highlighting a fundamental difference between developmental and regeneration patterning in the wing disc.
    DOI:  https://doi.org/10.1126/sciadv.ads5743
  17. Nat Commun. 2025 Jun 05. 16(1): 5226
    SWI/SNF ATPase silenced HLF potentiates lung metastasis in solid cancers.
    Jin Zhou, Austin Hepperla, Jeremy M Simon, Kangsan Kim, Qing Hu, Chuanhai Zhang, Lei Dong, Lianxin Hu, Cheng Zhang, Chengheng Liao, Alice Fang, Yayoi Adachi, Haoyong Fu, Tao Wang, Qian Liang, Fangzhou Zhao, Hongyi Liu, Masashi Takeda, Jun Fang, Hua Zhong, Peter Ly, Lu Wang, Payal Kapur, Lin Xu, Liwei Jia, Srinivas Malladi, James Brugarolas, M Celeste Simon, Bo Li, Qing Zhang.
      Metastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Here, using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conduct an in vivo genome-wide CRISPR-Cas9 screen and identify HLF as a potent suppressor of lung metastasis. HLF depletion enhances ccRCC cell migration and lung metastasis, whereas HLF overexpression abrogates these effects. In ccRCC patients, HLF expression is reduced at metastatic sites and associates with epigenetic silencing mediated by the SWI/SNF ATPase subunit BRG1. HLF levels negatively correlate with migration potential in collagen. Mechanistically, HLF regulates LPXN expression, modulating the integration of collagen's mechanical cues with the actin cytoskeleton through Paxillin, thereby suppressing cancer cell migration and lung metastasis. Overexpression of HLF or pharmacological inhibition of BRG1 reduces cell invasion across multiple cancer types. Our findings suggest that targeting the BRG1-HLF axis offers a promising therapeutic strategy for combating metastatic cancers.
    DOI:  https://doi.org/10.1038/s41467-025-60329-9
  18. Nucleic Acids Res. 2025 May 22. pii: gkaf457. [Epub ahead of print]53(10):
    Compromised two-start zigzag chromatin folding in immature mouse retina cells driven by irregularly spaced nucleosomes with short DNA linkers.
    Brianna Kable, Stephanie Portillo-Ledesma, Evgenya Y Popova, Nathan Jentink, Matthew Swulius, Zilong Li, Tamar Schlick, Sergei A Grigoryev.
      The formation of condensed heterochromatin is critical for establishing cell-specific transcriptional programs. To reveal structural transitions underlying heterochromatin formation in maturing mouse rod photoreceptors, we apply cryo-electron microscopy (cryo-EM) tomography, AI-assisted denoising, and molecular modeling. We find that chromatin isolated from immature retina cells contains many closely apposed nucleosomes with extremely short or absent nucleosome linkers, which are inconsistent with the typical two-start zigzag chromatin folding. In mature retina cells, the fraction of short-linker nucleosomes is much lower, supporting stronger chromatin compaction. By cryo-EM-assisted nucleosome interaction capture, we observe that chromatin in immature retina is enriched with i ± 1 interactions, while chromatin in mature retina contains predominantly i ± 2 interactions typical of the two-start zigzag. By mesoscale modeling and computational simulation, we clarify that the unusually short linkers typical of immature retina are sufficient to inhibit the two-start zigzag and chromatin compaction by the interference of very short linkers with linker DNA stems. We propose that this short linker composition renders nucleosome arrays more open in immature retina and that, as the linker DNA length increases in mature retina, chromatin becomes globally condensed via tight zigzag folding. This mechanism may be broadly utilized to introduce higher chromatin folding entropy for epigenomic plasticity.
    DOI:  https://doi.org/10.1093/nar/gkaf457
  19. Nat Commun. 2025 Jun 03. 16(1): 5138
    H3.3 deposition counteracts the replication-dependent enrichment of H3.1 at chromocenters in embryonic stem cells.
    S Arfè, T Karagyozova, A Forest, D Bingham, H Hmidan, D Mazaud, M Garnier, P Le Baccon, E Meshorer, J-P Quivy, G Almouzni.
      Chromocenters in mouse cells are membrane-less nuclear compartments representing typical heterochromatin stably maintained during cell cycle. We explore how histone H3 variants, replicative H3.1/2 or replacement H3.3, mark these domains during the cell cycle in mouse embryonic stem cells, neuronal precursor cells as well as immortalized 3T3 cells. We find a strong and distinct H3.1 enrichment at chromocenters, with variation in mouse embryonic stem cells. Mechanistically, this H3.1 selective enrichment depends on the DNA Synthesis Coupled deposition pathway operating in S phase challenged when we target H3.3 deposition through the DNA Synthesis Independent deposition pathway mediated by HIRA. Altering the H3.1/H3.3 dynamics at chromocenters in mouse embryonic stem cells affects nuclear morphology and cell division. Here, we reveal opposing mechanisms for H3.1 and H3.3 deposition with different enforcement according to cell cycle and potency which determine their ratio at chromocenters and are critical for genome stability and cell survival.
    DOI:  https://doi.org/10.1038/s41467-025-60430-z
  20. J Clin Invest. 2025 Jun 02. pii: e187490. [Epub ahead of print]135(11):
    PROX1 is an early driver of lineage plasticity in prostate cancer.
    Zhi Duan, Mingchen Shi, Anbarasu Kumaraswamy, Dong Lin, Dhruv Khokhani, Yong Wang, Chao Zhang, Diana Flores, Eva Rodansky, Olivia A Swaim, William K Storck, Hannah N Beck, Radhika A Patel, Erolcan Sayar, Brian P Hanratty, Hui Xue, Xin Dong, Zoe R Maylin, Rensheng Wan, David A Quigley, Martin Sjöström, Ya-Mei Hu, Faming Zhao, Zheng Xia, Siyuan Cheng, Xiuping Yu, Felix Y Feng, Li Zhang, Rahul Aggarwal, Eric J Small, Visweswaran Ravikumar, Arvind Rao, Karan Bedi, John K Lee, Colm Morrissey, Ilsa Coleman, Peter S Nelson, Eva Corey, Aaron M Udager, Ryan J Rebernick, Marcin P Cieslik, Arul M Chinnaiyan, Joel A Yates, Michael C Haffner, Yuzhuo Wang, Joshi J Alumkal.
      Lineage plasticity is recognized as a critical determinant of lethality and resistance to AR pathway inhibitors in prostate cancer. Lineage plasticity is a continuum, ranging from AR activity-low tumors, AR-null tumors that do not express a neuroendocrine prostate cancer (NEPC) program (i.e., double-negative prostate cancer [DNPC]), and AR-null NEPC tumors. Factors upregulated early in lineage plasticity are not well-characterized. The clarification of such factors is essential to identify tumors undergoing lineage plasticity or at risk of this occurring. Our integrative analysis of metastatic prostate cancer patient tumors, patient-derived xenografts, and cell models determined that PROX1 is upregulated early in the lineage plasticity continuum and progressively increases as tumors lose AR activity. We determined DNA methylation is a key regulator of PROX1 expression. PROX1 suppression in DNPC and NEPC reduces cell survival and impacts apoptosis and differentiation, demonstrating PROX1's functional importance. PROX1 is not directly targetable with standard drug development approaches. However, affinity immunopurification demonstrated histone deacetylases (HDACs) are among the top PROX1-interacting proteins; HDAC inhibition depletes PROX1 and recapitulates PROX1 suppression in DNPC and NEPC. Altogether, our results suggest PROX1 promotes the emergence of lineage plasticity, and HDAC inhibition is a promising approach to treat tumors across the lineage plasticity continuum.
    Keywords:  Cell biology; Epigenetics; Oncology; Prostate cancer
    DOI:  https://doi.org/10.1172/JCI187490
  21. Genome Res. 2025 Jun 02. pii: gr.280224.124. [Epub ahead of print]
    Androgen receptor-mediated assisted loading of the glucocorticoid receptor modulates transcriptional responses in prostate cancer cells.
    Johannes Hiltunen, Laura Helminen, Niina Aaltonen, Kaisa-Mari Launonen, Hanna Laakso, Marjo Malinen, Einari A Niskanen, Jorma J Palvimo, Ville Paakinaho.
      Steroid receptors are involved in a wide array of crosstalk mechanisms that regulate diverse biological processes, with significant implications in diseases, particularly in cancers. In prostate cancer, indirect crosstalk between androgen receptor (AR) and glucocorticoid receptor NR3C1 (also known as GR) is well-documented, wherein AR suppression by antiandrogen therapy leads to elevated GR levels, enabling GR to compensate for and replace AR signaling. However, the existence and impact of direct chromatin crosstalk between AR and GR in prostate cancer remain elusive. Our genome-wide investigations reveal that AR activation significantly expands GR chromatin binding. Mechanistically, AR induces remodeling of closed chromatin sites, facilitating GR binding to inaccessible sites. Importantly, coactivation of AR and GR results in distinct transcriptional responses at both the cell population and single-cell levels. Pathways affected by these transcriptional changes are generally associated with improved patient survival. Thus, the direct crosstalk between AR and GR yields markedly different outcomes from the known role of GR in circumventing AR blockade by antiandrogens.
    DOI:  https://doi.org/10.1101/gr.280224.124
  22. Sci Adv. 2025 Jun 06. 11(23): eadu9487
    Enhancer RNA-mediated transcriptional regulatory programs reveal the malignant progression of glioma.
    Yingying Ma, Shuyuan Wang, Yijie Jia, Shijie Wang, Wendian Liu, Jiaxin Yu, Jun Wang, Jingkai Geng, Jiayi Zhao, Zheng Zhao, Juan Xu, Hui Liu.
      To systematically investigate the molecular and pathological mechanisms of enhancer RNA (eRNA)-mediated transcriptional regulation in glioma recurrence and progression, transcriptomic, regulatome, and genomic data were integrated to analyze eRNA behavior in lower-grade gliomas (stages II/III) and glioblastomas (stage IV). Most eRNAs exhibited dynamic expression during glioma progression, regulated by master transcription factors (TFs) and affected by genomic mutations. The constructed perturbed TF-mediated eRNA-promoter regulatory landscape revealed that rewiring eRNA-promoter networks contributed to glioma malignancy. Drug response-related eRNAs associated with poor prognosis were identified, highlighting their clinical potential. Overall, integrative analysis highlights the critical role of eRNA-mediated regulatory rewiring in glioma progression, providing valuable insights into transcriptional mechanisms and potential therapeutic targets.
    DOI:  https://doi.org/10.1126/sciadv.adu9487
  23. Nat Commun. 2025 Jun 05. 16(1): 5236
    Direct detection of 8-oxo-dG using nanopore sequencing.
    Marc Pagès-Gallego, Daan M K van Soest, Nicolle J M Besselink, Roy Straver, Janneke P Keijer, Carlo Vermeulen, Alessio Marcozzi, Markus J van Roosmalen, Ruben van Boxtel, Boudewijn M T Burgering, Tobias B Dansen, Jeroen de Ridder.
      Genomic DNA is under constant oxidative damage, with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) being the prominent lesion linked to mutagenesis, epigenetics, and gene regulation. Existing methods to detect 8-oxo-dG rely on indirect approaches, while nanopore sequencing enables direct detection of base modifications. A model for 8-oxo-dG detection is currently missing due to the lack of training data. Here, we develop a strategy using synthetic oligos to generate long, 8-oxo-dG context-variable DNA molecules for deep learning and nanopore sequencing. Our training approach addresses the rarity of 8-oxo-dG relative to guanine, enabling specific detection. Applied to a tissue culture model of oxidative damage, our method reveals uneven genomic 8-oxo-dG distribution, dissimilar context pattern to C>A mutations, and local 5-mC depletion. This dual measurement of 5-mC and 8-oxo-dG at single-molecule resolution uncovers new insights into their interplay. Our approach also provides a general framework for detecting other rare DNA modifications using synthetic DNA and nanopore sequencing.
    DOI:  https://doi.org/10.1038/s41467-025-60391-3
  24. Sci Adv. 2025 Jun 06. 11(23): eadt3552
    HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism.
    Hyeyoung Nam, Anirban Kundu, Suman Karki, Richard L Kirkman, Darshan S Chandrashekar, Jeremy B Foote, Guofang Zhang, Wentao He, Sooryanarayana Varambally, Han-Fei Ding, Sunil Sudarshan.
      Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits notable metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, we demonstrate that HDAC7 promotes aggressive phenotypes and in vivo tumor progression in RCC. HDAC7 suppresses the expression of genes mediating branched-chain amino acid (BCAA) catabolism. Notably, lower expression of BCAA catabolism genes is strongly associated with worsened survival in ccRCC. Suppression of BCAA catabolism promotes expression of SNAIL1, a central mediator of aggressive phenotypes including migration and invasion. HDAC7-mediated suppression of the BCAA catabolic program promotes SNAI1 messenger RNA transcription via NOTCH signaling activation. Collectively, our findings provide innovative insights into the role of metabolic remodeling in ccRCC tumor progression.
    DOI:  https://doi.org/10.1126/sciadv.adt3552
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒16 at 10:39.