bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–02–09
23 papers selected by
Connor Rogerson, University of Cambridge
  1. Pioneer factor GATA6 promotes colorectal cancer through 3D genome regulation.
  2. A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations.
  3. PAX8 interacts with the SWI/SNF complex at enhancers to drive proliferation in ovarian cancer.
  4. Nuclear ANLN regulates transcription initiation related Pol II clustering and target gene expression.
  5. Multi-locus CRISPRi targeting with a single truncated guide RNA.
  6. RNA polymerase II coordinates histone deacetylation at active promoters.
  7. Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer.
  8. CoTF-reg reveals cooperative transcription factors in oligodendrocyte gene regulation using single-cell multi-omics.
  9. D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming.
  10. Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer.
  11. Effective in vivo binding energy landscape illustrates kinetic stability of RBPJ-DNA binding.
  12. Chromatin remodeler CHD4 establishes chromatin states required for ovarian reserve formation, maintenance and male germ cell survival.
  13. KMT2C/KMT2D-dependent H3K4me1 mediates changes in DNA replication timing and origin activity during a cell fate transition.
  14. An acidic residue within the OCT4 dimerization interface of SOX17 is necessary and sufficient to overcome its pluripotency-inducing activity.
  15. Single-stranded DNA binding to the transcription factor PafBC triggers the mycobacterial DNA damage response.
  16. Defining the regulatory logic of breast cancer using single-cell epigenetic and transcriptome profiling.
  17. HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis.
  18. Histone H3E50K remodels chromatin to confer oncogenic activity and support an EMT phenotype.
  19. Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus.
  20. SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.
  21. The zinc-finger transcription factor Blimp1/Prdm1 is required for uterine remodelling and repair in the mouse.
  22. OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma.
  23. The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2.
  1. Sci Adv. 2025 Feb 07. 11(6): eads4985
    Pioneer factor GATA6 promotes colorectal cancer through 3D genome regulation.
    Huijue Lyu, Xintong Chen, Yang Cheng, Te Zhang, Ping Wang, Josiah Hiu-Yuen Wong, Juan Wang, Lena Stasiak, Leyu Sun, Guangyu Yang, Lu Wang, Feng Yue.
      Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies. While the overexpression of pioneer factor GATA6 in CRC has been linked with metastasis, its role in genome-wide gene expression dysregulation remains unclear. Through studies of primary human CRC tissues and analysis of the TCGA data, we found that GATA6 preferentially binds at CRC-specific active enhancers, with enrichment at enhancer-promoter loop anchors. GATA6 protein also physically interacts with CTCF, suggesting its critical role in 3D genome organization. The ablation of GATA6 through AID and CRISPR systems severely impaired cancer cell clonogenicity and proliferation. Mechanistically, GATA6 knockout induced global loss of CRC-specific open chromatins and extensive alterations of critical enhancer-promoter interactions for CRC oncogenes. Last, we showed that GATA6 knockout greatly reduced tumor growth and improved survival in mice. Together, we revealed a previously unidentified mechanism by which GATA6 contributes to the pathogenesis of colorectal cancer.
    DOI:  https://doi.org/10.1126/sciadv.ads4985
  2. Nat Commun. 2025 Feb 05. 16(1): 1377
    A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations.
    Yorihiro Iwasaki, Monica Reyes, Harald Jüppner, Murat Bastepe.
      Genomic imprinting controls parental allele-specific gene expression via epigenetic mechanisms. Abnormal imprinting at the GNAS gene causes multiple phenotypes, including pseudohypoparathyroidism type-1B (PHP1B), a disorder of multihormone resistance. Microdeletions affecting the neighboring STX16 gene ablate an imprinting control region (STX16-ICR) of GNAS and lead to PHP1B upon maternal but not paternal inheritance. Mechanisms behind this imprinted inheritance mode remain unknown. Here, we show that the STX16-ICR forms different chromatin conformations with each GNAS parental allele and enhances two GNAS promoters in human embryonic stem cells. When these cells differentiate toward proximal renal tubule cells, STX16-ICR loses its effect, accompanied by a transition to a somatic cell-specific GNAS imprinting status. The activity of STX16-ICR depends on an OCT4 motif, whose disruption impacts transcript levels differentially on each allele. Therefore, a biallelically active embryonic enhancer dictates GNAS imprinting via different chromatin conformations, underlying the allele-specific pathogenicity of STX16-ICR microdeletions.
    DOI:  https://doi.org/10.1038/s41467-025-56608-0
  3. Mol Cancer Res. 2025 Feb 07.
    PAX8 interacts with the SWI/SNF complex at enhancers to drive proliferation in ovarian cancer.
    Kostianna Sereti, Anna E Russo, Ryan Raisner, Taylur P Ma, Karen E Gascoigne.
      Activation of lineage-specific gene expression programs is mediated by recruitment of lineage-specific transcription factors and their coactivators to chromatin. The lineage factor PAX8 drives essential gene expression in ovarian cancer cells and is required for tumor proliferation. However, the molecular details surrounding co-factor recruitment and specific activation of transcription by PAX8 remain unknown. Here, we identify an important functional interaction between PAX8 and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. We show that PAX8 can recruit SWI/SNF complexes to DNA, where they function to open chromatin and facilitate expression of PAX8 target genes. Genetic deletion of PAX8 results in loss of SWI/SNF from PAX8 bound enhancers, loss of expression of associated target genes, and reduced proliferation. These results can be phenocopied by pharmacological inhibition of SWI/SNF ATPase activity. These data indicate that PAX8 mediates the expression of an essential ovarian cancer proliferative program in part by the recruitment of the SWI/SNF complex, highlighting a novel vulnerability in PAX8 dependent ovarian cancer. Implications: PAX8 recruits SWI/SNF complexes to enhancers, to mediate expression of genes essential for ovarian cancer proliferation.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-0710
  4. Nat Commun. 2025 Feb 02. 16(1): 1271
    Nuclear ANLN regulates transcription initiation related Pol II clustering and target gene expression.
    Yu-Fei Cao, Hui Wang, Yong Sun, Bei-Bei Tong, Wen-Qi Shi, Liu Peng, Yi-Meng Zhang, Yu-Qiu Wu, Teng Fu, Hua-Yan Zou, Kai Zhang, Li-Yan Xu, En-Min Li.
      Anillin (ANLN), a mitotic protein that regulates contractile ring assembly, has been reported as an oncoprotein. However, the function of ANLN in cancer cells, especially in the nucleus, has not been fully understood. Here, we report a role of nuclear ANLN in gene transcriptional regulation. We find that nuclear ANLN directly interacts with the RNA polymerase II (Pol II) large subunit to form transcriptional condensates. ANLN enhances initiated Pol II clustering and promotes Pol II CTD phase separation. Short-term depletion of ANLN alters the chromatin binding and enhancer-mediated transcriptional activity of Pol II. The target genes of ANLN-Pol II axis are involved in oxidoreductase activity, Wnt signaling and cell differentiation. THZ1, a super-enhancer inhibitor, specifically inhibits ANLN-Pol II clustering, target gene expression and esophageal squamous cell carcinoma (ESCC) cell proliferation. Our results reveal the function of nuclear ANLN in transcriptional regulation, providing a theoretical basis for ESCC treatment.
    DOI:  https://doi.org/10.1038/s41467-025-56645-9
  5. Nat Commun. 2025 Feb 04. 16(1): 1357
    Multi-locus CRISPRi targeting with a single truncated guide RNA.
    Molly M Moore, Siddarth Wekhande, Robbyn Issner, Alejandro Collins, Anna J Cruz, Yanjing V Liu, Nauman Javed, Salvador Casaní-Galdón, Jason D Buenrostro, Charles B Epstein, Eugenio Mattei, John G Doench, Bradley E Bernstein, Noam Shoresh, Fadi J Najm.
      A critical goal in functional genomics is evaluating which non-coding elements contribute to gene expression, cellular function, and disease. Functional characterization remains a challenge due to the abundance and complexity of candidate elements. Here, we develop a CRISPRi-based approach for multi-locus screening of putative transcription factor binding sites with a single truncated guide. A truncated guide with hundreds of sequence match sites can reliably disrupt enhancer activity, which expands the targeting scope of CRISPRi while maintaining repressive efficacy. We screen over 13,000 possible CTCF binding sites with 24 guides at 10 nucleotides in spacer length. These truncated guides direct CRISPRi-mediated deposition of repressive H3K9me3 marks and disrupt transcription factor binding at most sequence match target sites. This approach can be a valuable screening step for testing transcription factor binding motifs or other repeated genomic sequences and is easily implemented with existing tools.
    DOI:  https://doi.org/10.1038/s41467-025-56144-x
  6. Sci Adv. 2025 Feb 07. 11(6): eadt3037
    RNA polymerase II coordinates histone deacetylation at active promoters.
    Jackson A Hoffman, Kevin W Trotter, Trevor K Archer.
      Nucleosomes at promoters of active genes are marked by specific histone post-translational modifications and histone variants. These features are thought to promote the formation and maintenance of an "open" chromatin environment that is suitable for transcription. However, recent reports have drawn conflicting conclusions about whether these histone modifications depend on active transcription. To further interrogate this relationship, we inhibited transcription initiation using triptolide, which triggered degradation of RNA polymerase II, and examined the impact on histone modifications. Transcription initiation was not required for either hormone-induced or steady-state active histone modifications at transcription start sites (TSSs) and enhancers. Rather, blocking transcription initiation increased the levels of histone acetylation and H2AZ incorporation at active TSSs. P300 activity was dispensable for this effect, but inhibition of histone deacetylases masked the increased acetylation. Together, our results demonstrate that active histone modifications occur independently of transcription. Furthermore, our findings suggest that the process of transcription coordinates the removal of these modifications to limit gene activity.
    DOI:  https://doi.org/10.1126/sciadv.adt3037
  7. Cell Rep. 2025 Feb 04. pii: S2211-1247(25)00038-5. [Epub ahead of print]44(2): 115267
    Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer.
    Parik Kakani, Shruti Ganesh Dhamdhere, Deepak Pant, Rushikesh Joshi, Sachin Mishra, Anchala Pandey, Dimple Notani, Sanjeev Shukla.
      Hypoxia influences the epithelial-mesenchymal transition (EMT) through the remodeling of the chromatin structure, epigenetics, and alternative splicing. Hypoxia drives CCCTC-binding factor (CTCF) induction through hypoxia-inducible factor 1-alpha (HIF1α), which promotes EMT, although the underlying mechanisms remain unclear. We find that hypoxia significantly increases CTCF occupancy at various EMT-related genes. We present a CTCF-mediated intricate mechanism promoting EMT wherein CTCF binding at the collagen type V alpha 1 chain (COL5A1) promoter is crucial for COL5A1 upregulation under hypoxia. Additionally, hypoxia drives exon64A inclusion in a mutually exclusive alternative splicing event of COL5A1exon64 (exon64A/64B). Notably, CTCF mediates COL5A1 promoter-alternatively spliced exon upstream looping that regulates DNA demethylation at distal exon64A. This further regulates the CTCF-mediated RNA polymerase II pause at COL5A1exon64A, leading to its inclusion in promoting the EMT under hypoxia. Genome-wide study indicates the association of gained CTCF occupancy with the alternative splicing of many cancer-related genes, similar to the proposed model. Specifically, disrupting the HIF1α-CTCF-COL5A1exon64A axis through the dCas9-DNMT3A system alleviates the EMT in hypoxic cancer cells and may represent a novel therapeutic target in breast cancer.
    Keywords:  COL5A1; CP: Cancer; CP: Molecular biology; CRISPR-dCas9-mediated editing; CTCF; EMT; alternative splicing; breast cancer; epigenetics; hypoxia; promoter-exon upstream looping
    DOI:  https://doi.org/10.1016/j.celrep.2025.115267
  8. Commun Biol. 2025 Feb 05. 8(1): 181
    CoTF-reg reveals cooperative transcription factors in oligodendrocyte gene regulation using single-cell multi-omics.
    Jerome J Choi, John Svaren, Daifeng Wang.
      Oligodendrocytes are the myelinating cells within the central nervous system, but the mechanisms by which transcription factors (TFs) cooperate for gene regulation in oligodendrocytes remain unclear. We introduce coTF-reg, an analytical framework that integrates scRNA-seq and scATAC-seq data to identify cooperative TFs co-regulating the target gene (TG). First, we identify co-binding TF pairs in the same oligodendrocyte-specific regulatory regions. Next, we train a deep learning model to predict each TG expression using the co-binding TFs' expressions. Shapley interaction scores reveal high interactions between co-binding TF pairs, such as SOX10-TCF12. Validation using oligodendrocyte eQTLs and their eGenes that are regulated by these cooperative TFs show potential regulatory roles for genetic variants. Experimental validation using ChIP-seq data confirms some cooperative TF pairs, such as SOX10-OLIG2. Prediction performance of our models is evaluated through holdout data and additional datasets, and an ablation study is also conducted. The results demonstrate stable and consistent performance.
    DOI:  https://doi.org/10.1038/s42003-025-07570-6
  9. Nat Commun. 2025 Feb 07. 16(1): 1431
    D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming.
    Fengchao Lang, Karambir Kaur, Haiqing Fu, Javeria Zaheer, Diego Luis Ribeiro, Mirit I Aladjem, Chunzhang Yang.
      Cancer-associated mutations in IDH are associated with multiple types of human malignancies, which exhibit distinctive metabolic reprogramming, production of oncometabolite D-2-HG, and shifted epigenetic landscape. IDH mutated malignancies are signatured with "BRCAness", highlighted with the sensitivity to DNA repair inhibitors and genotoxic agents, although the underlying molecular mechanism remains elusive. In the present study, we demonstrate that D-2-HG impacts the chromatin conformation adjustments, which are associated with DNA repair process. Mechanistically, D-2-HG diminishes the chromatin interactions in the DNA damage regions via revoking CTCF binding. The hypermethylation of cytosine, resulting from the suppression of TET1 and TET2 activities by D-2-HG, contributes to the dissociation of CTCF from DNA damage regions. CTCF depletion leads to the disruption of chromatin organization around the DNA damage sites, which abolishes the recruitment of essential DNA damage repair proteins BRCA2 and RAD51, as well as impairs homologous repair in the IDH mutant cancer cells. These findings provide evidence that CTCF-mediated chromatin interactions play a key role in DNA damage repair proceedings. Oncometabolites jeopardize genome stability and DNA repair by affecting high-order chromatin structure.
    DOI:  https://doi.org/10.1038/s41467-025-56781-2
  10. Commun Biol. 2025 Feb 04. 8(1): 169
    Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer.
    Bengul Gokbayrak, Umut Berkay Altintas, Shreyas Lingadahalli, Tunc Morova, Chia-Chi Flora Huang, Betul Ersoy Fazlioglu, Ivan Pak Lok Yu, Batuhan M Kalkan, Paloma Cejas, Sonia H Y Kung, Ladan Fazli, Akane Kawamura, Henry W Long, Ceyda Acilan, Tamer T Onder, Tugba Bagci-Onder, James T Lynch, Nathan A Lack.
      Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there is strong evidence that epigenetic factors can cause enzalutamide resistance. To explore how resistance arises, we systematically test all epigenetic modifiers in several models of castration-resistant and enzalutamide-resistant prostate cancer with a custom epigenetic CRISPR library. From this, we identify and validate SMARCC2, a core component of the SWI/SNF complex, that is selectivity essential in enzalutamide-resistant models. We show that the chromatin occupancy of SMARCC2 and BRG1 is expanded in enzalutamide resistance at regions that overlap with CRPC-associated transcription factors that are accessible in CRPC clinical samples. Overall, our study reveals a regulatory role for SMARCC2 in enzalutamide-resistant prostate cancer and supports the feasibility of targeting the SWI/SNF complex in late-stage PCa.
    DOI:  https://doi.org/10.1038/s42003-024-07413-w
  11. Nat Commun. 2025 Feb 01. 16(1): 1259
    Effective in vivo binding energy landscape illustrates kinetic stability of RBPJ-DNA binding.
    Duyen Huynh, Philipp Hoffmeister, Tobias Friedrich, Kefan Zhang, Marek Bartkuhn, Francesca Ferrante, Benedetto Daniele Giaimo, Rhett A Kovall, Tilman Borggrefe, Franz Oswald, J Christof M Gebhardt.
      Transcription factors (TFs) such as RBPJ in Notch signaling bind to specific DNA sequences to regulate transcription. How TF-DNA binding kinetics and cofactor interactions modulate gene regulation is mostly unknown. We determine the binding kinetics, transcriptional activity, and genome-wide chromatin occupation of RBPJ and mutant variants by live-cell single-molecule tracking, reporter assays, and ChIP-Seq. Importantly, the search time of RBPJ exceeds its residence time, indicating kinetic rather than thermodynamic binding stability. Impaired RBPJ-DNA binding as in Adams-Oliver-Syndrome affect both target site association and dissociation, while impaired cofactor binding mainly alters association and unspecific binding. Moreover, our data point to the possibility that cofactor binding contributes to target site specificity. Findings for other TFs comparable to RBPJ indicate that kinetic rather than thermodynamic DNA binding stability might prevail in vivo. We propose an effective in vivo binding energy landscape of TF-DNA interactions as instructive visualization of binding kinetics and mutation-induced changes.
    DOI:  https://doi.org/10.1038/s41467-025-56515-4
  12. Nucleic Acids Res. 2025 Jan 24. pii: gkaf008. [Epub ahead of print]53(3):
    Chromatin remodeler CHD4 establishes chromatin states required for ovarian reserve formation, maintenance and male germ cell survival.
    Yasuhisa Munakata, Mengwen Hu, Yuka Kitamura, Raissa G Dani, Adam L Bynder, Amelia S Fritz, Richard M Schultz, Satoshi H Namekawa.
      The ovarian reserve defines female reproductive lifespan, which in humans spans decades due to the maintenance of meiotic arrest in non-growing oocytes (NGOs) residing in primordial follicles. Unknown is how the chromatin state of NGOs is established to enable long-term maintenance of the ovarian reserve. Here, we show that a chromatin remodeler, CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, establishes chromatin states required for formation and maintenance of the ovarian reserve. Conditional loss of CHD4 in perinatal mouse oocytes results in acute death of NGOs and depletion of the ovarian reserve. CHD4 establishes closed chromatin at regulatory elements of pro-apoptotic genes to prevent cell death and at specific genes required for meiotic prophase I to facilitate the transition from meiotic prophase I oocytes to meiotically-arrested NGOs. In male germ cells, CHD4 establishes closed chromatin at the regulatory elements of pro-apoptotic genes, allowing germ cell survival. These results demonstrate a role for CHD4 in defining a chromatin state that ensures germ cell survival, thereby enabling the long-term maintenance of both female and male germ cells.
    DOI:  https://doi.org/10.1093/nar/gkaf008
  13. Cell Rep. 2025 Feb 04. pii: S2211-1247(25)00043-9. [Epub ahead of print]44(2): 115272
    KMT2C/KMT2D-dependent H3K4me1 mediates changes in DNA replication timing and origin activity during a cell fate transition.
    Deniz Gökbuget, Liana Goehring, Ryan M Boileau, Kayla Lenshoek, Tony T Huang, Robert Blelloch.
      Mammalian genomes replicate in a cell-type-specific order during the S phase, correlated to transcriptional activity, histone modifications, and chromatin structure. The causal relationships between these features and DNA replication timing (RT), especially during cell fate changes, are largely unknown. Using machine learning, we quantify 21 chromatin features predicting local RT and RT changes during differentiation in embryonic stem cells (ESCs). About one-third of the genome shows RT changes during differentiation. Chromatin features accurately predict both steady-state RT and RT changes. Histone H3 lysine 4 monomethylation (H3K4me1), catalyzed by KMT2C and KMT2D (KMT2C/D), emerges as a top predictor. Loss of KMT2C/D or their enzymatic activities impairs RT changes during differentiation. This correlates with local H3K4me1 loss and reduced replication origin firing, while transcription remains largely unaffected. Our findings reveal KMT2C/D-dependent H3K4me1 as a key regulator of RT and replication initiation, a role that likely impacts diseases associated with KMT2C/D mutations.
    Keywords:  CP: Molecular biology; DNA replication domains; H3K4 monomethylation; KMT2C; KMT2D; MLL3; MLL4; cell cycle; cell fate; chromatin features; epiblast-like cells; epigenetics; formative; genomics; histone modifications; initiation zones; machine learning; naive; pluripotency; predictive modeling; replication origins; replication timing; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2025.115272
  14. Stem Cell Reports. 2025 Jan 23. pii: S2213-6711(25)00002-5. [Epub ahead of print] 102398
    An acidic residue within the OCT4 dimerization interface of SOX17 is necessary and sufficient to overcome its pluripotency-inducing activity.
    Sik Yin Ho, Haoqing Hu, Derek Hoi Hang Ho, Allan Patrick Stephane Renom, Shi Wing Yeung, Freya Boerner, Mingxi Weng, Andrew Paul Hutchins, Ralf Jauch.
      SOX17 directs the differentiation toward endoderm and acts as a human germline specifier. We previously found that the replacement of glutamate at position 57 of the high-mobility group (HMG) box with the basic lysine residue in SOX2 alters interactions with OCT4 and turns SOX17 into a pluripotency factor. Here, we systematically interrogated how mutations at this critical position affect the cellular reprogramming activity of SOX17 in mouse and human. We found that most mutations turn SOX17 into a pluripotency factor regardless of their biophysical properties except for acidic residues and proline. The conservative mutation to an aspartate allows the SOX17E57D protein to maintain a self-renewing endodermal state. We showed that only the glutamate in the wild-type protein blocks the formation of an SOX17/OCT4 dimer at composite DNA elements in pluripotency enhancers. Insights into how modifications of an ultra-conserved residue affect functions of developmental transcription factors provide avenues to advance cell fate engineering.
    Keywords:  SOX17; SOX2; XEN; engineered proteins; iPSCs; pioneer factors; pluripotency; reprogramming
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102398
  15. Sci Adv. 2025 Feb 07. 11(6): eadq9054
    Single-stranded DNA binding to the transcription factor PafBC triggers the mycobacterial DNA damage response.
    Charlotte M Schilling, Rafal Zdanowicz, Julius Rabl, Andreas U Müller, Daniel Boehringer, Rudi Glockshuber, Eilika Weber-Ban.
      The DNA damage response in mycobacteria is controlled by the heterodimeric transcription factor PafBC, a member of the WYL domain-containing protein family. It has been shown that PafBC induces transcription of its regulon by reprogramming the housekeeping RNA polymerase holoenzyme to recognize PafBC-dependent promoters through sigma adaptation. However, the mechanism by which DNA damage is sensed and translated into PafBC activation has remained unclear. Here, we demonstrate that the binding of single-stranded DNA (ssDNA) to the WYL domains of PafBC activates the transcription factor. Our cryo-electron microscopy structure of full-length PafBC in its active conformation, bound to the transcription initiation complex, reveals a previously unknown mode of interaction between the ssDNA and the WYL domains. Using biochemical experiments, we show that short ssDNA fragments bind to PafBC dynamically, resulting in deactivation as ssDNA levels decrease postrepair. Our findings shed light on the mechanism linking DNA damage to PafBC activation and expand our understanding of WYL domain-containing proteins.
    DOI:  https://doi.org/10.1126/sciadv.adq9054
  16. Cell Genom. 2025 Jan 28. pii: S2666-979X(25)00021-7. [Epub ahead of print] 100765
    Defining the regulatory logic of breast cancer using single-cell epigenetic and transcriptome profiling.
    Matthew J Regner, Susana Garcia-Recio, Aatish Thennavan, Kamila Wisniewska, Raul Mendez-Giraldez, Brooke Felsheim, Philip M Spanheimer, Joel S Parker, Charles M Perou, Hector L Franco.
      Annotation of cis-regulatory elements that drive transcriptional dysregulation in cancer cells is critical to understanding tumor biology. Herein, we present matched chromatin accessibility (single-cell assay for transposase-accessible chromatin by sequencing [scATAC-seq]) and transcriptome (single-cell RNA sequencing [scRNA-seq]) profiles at single-cell resolution from human breast tumors and healthy mammary tissues processed immediately following surgical resection. We identify the most likely cell of origin for subtype-specific breast tumors and implement linear mixed-effects modeling to quantify associations between regulatory elements and gene expression in malignant versus normal cells. These data unveil cancer-specific regulatory elements and putative silencer-to-enhancer switching events in cells that lead to the upregulation of clinically relevant oncogenes. In addition, we generate matched scATAC-seq and scRNA-seq profiles for breast cancer cell lines, revealing a conserved oncogenic gene expression program between in vitro and in vivo cells. This work highlights the importance of non-coding regulatory mechanisms that underlie oncogenic processes and the ability of single-cell multi-omics to define the regulatory logic of cancer cells.
    Keywords:  breast cancer; chromatin accessibility; enhancer elements; gene regulation; scATAC-seq; scRNA-seq; single-cell genomics; single-cell multi-omics
    DOI:  https://doi.org/10.1016/j.xgen.2025.100765
  17. J Clin Invest. 2025 Feb 03. pii: e184442. [Epub ahead of print]135(3):
    HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis.
    Li Z Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L Reddy, Ying Feng, Eric R Fearon, Cynthia L Sears, Linda Resar.
      Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 "opens" chromatin to upregulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas reexpression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.
    Keywords:  Colorectal cancer; Epigenetics; Oncology; Transcription
    DOI:  https://doi.org/10.1172/JCI184442
  18. NAR Cancer. 2025 Mar;7(1): zcaf002
    Histone H3E50K remodels chromatin to confer oncogenic activity and support an EMT phenotype.
    Kirti Sad, Dorelle V Fawwal, Celina Y Jones, Emily J Hill, Katie T Skinner, Miranda L Adams, Severin Lustenberger, Richard S Lee, Sandhya V Lohano, Satvik R Elayavalli, Jonathan Farhi, Christina C Mehta, Laramie D Lemon, Milo B Fasken, Andrew L Hong, Steven A Sloan, Anita H Corbett, Jennifer M Spangle.
      Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype. Expression of H3E50K is sufficient to transform human cells as evidenced by an increase in cell migration and invasion, and an increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K selectively increases chromatin accessibility and perturbs proximal H3 post-translational modifications including H3K27me3; together these changes to chromatin dynamics dysregulate gene expression to support the epithelial-to-mesenchymal transition. Functional studies using Saccharomyces cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional H3 mutations have the potential to support oncogenic activity and function through distinct mechanisms that dysregulate gene expression.
    DOI:  https://doi.org/10.1093/narcan/zcaf002
  19. Science. 2025 Feb 07. 387(6734): eadm9466
    Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus.
    Léa Meneu, Christophe Chapard, Jacques Serizay, Alex Westbrook, Etienne Routhier, Myriam Ruault, Manon Perrot, Alexandros Minakakis, Fabien Girard, Amaury Bignaud, Antoine Even, Géraldine Gourgues, Domenico Libri, Carole Lartigue, Aurèle Piazza, Agnès Thierry, Angela Taddei, Frédéric Beckouët, Julien Mozziconacci, Romain Koszul.
      In eukaryotes, DNA-associated protein complexes coevolve with genomic sequences to orchestrate chromatin folding. We investigate the relationship between DNA sequence and the spontaneous loading and activity of chromatin components in the absence of coevolution. Using bacterial genomes integrated into Saccharomyces cerevisiae, which diverged from yeast more than 2 billion years ago, we show that nucleosomes, cohesins, and associated transcriptional machinery can lead to the formation of two different chromatin archetypes, one transcribed and the other silent, independently of heterochromatin formation. These two archetypes also form on eukaryotic exogenous sequences, depend on sequence composition, and can be predicted using neural networks trained on the native genome. They do not mix in the nucleus, leading to a bipartite nuclear compartmentalization, reminiscent of the organization of vertebrate nuclei.
    DOI:  https://doi.org/10.1126/science.adm9466
  20. Genome Biol. 2025 Feb 05. 26(1): 22
    SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.
    Ryan T Wagner, Ryan A Hlady, Xiaoyu Pan, Liguo Wang, Sungho Kim, Xia Zhao, Louis Y El Khoury, Shafiq Shaikh, Jian Zhong, Jeong-Heon Lee, Jolanta Grembecka, Tomasz Cierpicki, Thai H Ho, Keith D Robertson.
       BACKGROUND: SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating cellular processes such as RNA splicing, DNA repair, and spurious transcription initiation underlies its broader tumor suppressor function. SETD2 mutation promotes the epithelial-mesenchymal transition and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation.
    RESULTS: We employ an unbiased genome-wide synthetic lethal screen, which identifies another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction is performed in isogenic clear cell renal cell carcinoma and immortalized renal epithelial cell lines, in mouse and human backgrounds. Depletion of NSD1 using a CRISPRi targeting approach promotes the loss of SETD2-mutant cells coincident with elevated levels of DNA damage and apoptosis. Surprisingly, only suppression of NSD1, but not related H3K36-methyltransferases, promotes synthetic lethality in these models. Mapping of genomic H3K36me2 targeting by NSD1 and NSD2 individually highlights the independent functions of these epigenetic writers. Furthermore, as a proof-of-principle, we demonstrate the therapeutic feasibility of targeting this synthetic lethal interaction by recapitulating the phenotype using BT5, a first-in-class pharmacologic inhibitor against NSD1.
    CONCLUSIONS: These findings unify genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach to individualize therapies against a challenging loss-of-function SETD2 mutation in cancer.
    Keywords:  CRISPRi; Clear cell renal cell carcinoma (ccRCC); Epithelial-mesenchymal transition (EMT); Histone 3, lysine 36, tri-methylation (H3K36me3); Homologous recombination (HR); Homology-directed repair (HDR); NSD1; SETD2; Synthetic lethality (SL)
    DOI:  https://doi.org/10.1186/s13059-025-03483-z
  21. Nat Commun. 2025 Jan 31. 16(1): 1220
    The zinc-finger transcription factor Blimp1/Prdm1 is required for uterine remodelling and repair in the mouse.
    Maria-Eleni Xypolita, Mubeen Goolam, Elizabeth K Bikoff, Elizabeth J Robertson, Arne W Mould.
      The zinc finger transcription factor Blimp1/PRDM1 regulates gene expression in diverse cell types. Its activity controls the maternal decidual response at early post-implantation stages of development. The present experiments demonstrate surprisingly that Blimp1 activity in the uterus is required for tissue remodelling at sites of embryonic failure. Moreover Blimp1 mutant females are refractory to RU486 induced decidual shedding. RNA-seq together with immunostaining experiments strongly suggest that the failure to up-regulate expression of the matrix metalloprotease Mmp10 in combination with insufficient suppression of BMP signalling, likely explain Blimp1-dependent phenotypic changes. In the post-partum uterus Blimp1 together with Mmp10 are highly upregulated at sites of tissue repair following placental detachment. Conditional Blimp1 removal significantly impairs the re-epithelization process and severely impacts involution of the endometrium and luminal epithelium. Overall these results identify Blimp1 as a master regulator of uterine tissue remodelling and repair.
    DOI:  https://doi.org/10.1038/s41467-025-56511-8
  22. Nat Commun. 2025 Feb 04. 16(1): 1092
    OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma.
    Kinjal Desai, Siyi Wanggou, Erika Luis, Heather Whetstone, Chunying Yu, Robert J Vanner, Hayden J Selvadurai, Lilian Lee, Jinchu Vijay, Julia E Jaramillo, Jerry Fan, Paul Guilhamon, Michelle Kushida, Xuejun Li, Gregory Stein, Santosh Kesari, Benjamin D Simons, Xi Huang, Peter B Dirks.
      Functional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of which is defined by characteristically quiescent SOX2+ stem-like cells. Integrating gene expression and chromatin accessibility patterns in distinct cellular compartments, we identify the transcription factor Olig2 as regulating the stem cell fate transition from quiescence to activation, driving the generation of downstream neoplastic progenitors. Inactivation of Olig2 blocks stem cell activation and tumour output. Targeting this rare OLIG2-driven proliferative programme with a small molecule inhibitor, CT-179, dramatically attenuates early tumour formation and tumour regrowth post-therapy, and significantly increases median survival in vivo. We demonstrate that targeting transition from quiescence to proliferation at the level of the tumorigenic cell could be a pivotal medulloblastoma treatment strategy.
    DOI:  https://doi.org/10.1038/s41467-024-54858-y
  23. Elife. 2025 Feb 04. pii: RP97577. [Epub ahead of print]13
    The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2.
    Adam D Longhurst, Kyle Wang, Harsha Garadi Suresh, Mythili Ketavarapu, Henry N Ward, Ian R Jones, Vivek Narayan, Frances V Hundley, Arshia Zernab Hassan, Charles Boone, Chad L Myers, Yin Shen, Vijay Ramani, Brenda J Andrews, David P Toczyski.
      Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenetic approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued proliferation inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in antagonizing G1 progression in a diversity of cell linages, including chronic myeloid leukemia (CML), breast cancer, and immortalized cell lines.
    Keywords:  D-type cyclins; cell biology; cell cycle; genetics; genomics; human; molecular biology; palbociclib
    DOI:  https://doi.org/10.7554/eLife.97577
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