bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–10–26
fifteen papers selected by
Connor Rogerson, University of Cambridge
  1. Deciphering histone mark-specific fine-scale chromatin organization at high resolution with Micro-C-ChIP.
  2. Transcriptional condensates encode a "golden mean" to optimize enhancer-promoter communication across genomic distances.
  3. iNOME-seq: in vivo simultaneous genome-wide mapping of chromatin accessibility, nucleosome positioning, DNA-binding protein sites, and DNA methylation in Arabidopsis.
  4. Refined mechanism of promoter nucleosome-depleted regions resetting after replication.
  5. Cell-type-specific RNA polymerase II activity maps in intact tissues provide a gateway to mammalian gene regulatory mechanisms in vivo.
  6. Enhancer activation from transposable elements in extrachromosomal DNA.
  7. Activity of the SWI/SNF complex is indispensable for syncytiotrophoblast formation.
  8. EZHIP restricts noncanonical PRC2 binding and regulates H3K27me3 intergenerational inheritance and reprogramming.
  9. Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification.
  10. Characterization of core promoter activation by the Drosophila insulator-binding protein BEAF.
  11. Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.
  12. Chromatin activity of IκBα mediates the exit from naïve pluripotency.
  13. Sequential verification of transcription by Integrator and Restrictor.
  14. scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution.
  15. MED1 IDR deacetylation controls stress responsive genes through RNA Pol II recruitment.
  1. Nat Commun. 2025 Oct 22. 16(1): 9331
    Deciphering histone mark-specific fine-scale chromatin organization at high resolution with Micro-C-ChIP.
    Mariia Metelova, Maria Louisa Vigh, Nils Krietenstein.
      The regulation of cell-type-specific transcription relies on complex 3D interactions between promoters and distal regulatory elements. Although Hi-C has advanced our understanding of genome architecture, its high sequencing demand limits use in large-scale or time course experiments. We introduce Micro-C-ChIP, a strategy combining Micro-C with chromatin immunoprecipitation to map 3D genome organization at nucleosome resolution for defined histone modifications. We profile H3K4me3 and H3K27me3-specific 3D genome architecture in mouse embryonic stem cells (mESC), hTERT-immortalized human retinal pigment epithelial (hTERT-RPE1) cells, and HCT-116 RAD21-mAID-mClover (HCT-116 RAD21-mAC) cells. We validate that Micro-C-ChIP reveals genuine 3D genome features that are not driven by ChIP-enrichment bias. We identify extensive promoter-promoter contact networks in mESCs and hTERT-RPE1, and resolve the distinct 3D architecture of bivalent promoters in mESCs. Together, our results demonstrate that Micro-C-ChIP is a high-resolution, cost-efficient approach to study histone-modification-specific chromatin folding.
    DOI:  https://doi.org/10.1038/s41467-025-64350-w
  2. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2513371122
    Transcriptional condensates encode a "golden mean" to optimize enhancer-promoter communication across genomic distances.
    Tao Zhu, Chunhe Li, Xiakun Chu.
      Enhancers regulate gene expression by physically contacting their target promoters, yet these contacts often span large genomic distances. Phase-separated condensates (droplet-like clusters) of transcription factors (TFs) are thought to facilitate such long-range enhancer-promoter (E-P) communication, but the quantitative principles underlying this mechanism remain unclear. Here, we use polymer-based chromatin simulations to systematically vary the strength of TF clustering and the E-P genomic distance, examining their combined effects on E-P contact formation. We find that E-P contact frequency shows a nonmonotonic dependence on the degree of TF clustering: Contact frequency peaks at an intermediate TF abundance and TF-TF affinity, leading to a "golden mean" optimum. Two distinct regimes emerge: Under weak TF-TF attraction, contact probability increases with condensate size, whereas strong TF attraction produces a peaked response that declines at high condensation levels. These results indicate that TF condensate acts as a tunable "rheostat," buffering E-P interactions against increasing genomic distances. However, excessive TF clustering leads to molecular crowding and competition that ultimately impair E-P communication. Our study, consistent with recent experiments, establishes a mechanistic framework at the molecular level, where balanced TF condensation enables robust long-range E-P communication, reconciling the stochastic nature of chromatin dynamics with the fidelity of gene regulation.
    Keywords:  4D genome; coarse-grained models; phase separation; structure–dynamics–function relationship; transcriptional cluster
    DOI:  https://doi.org/10.1073/pnas.2513371122
  3. Genome Biol. 2025 Oct 22. 26(1): 361
    iNOME-seq: in vivo simultaneous genome-wide mapping of chromatin accessibility, nucleosome positioning, DNA-binding protein sites, and DNA methylation in Arabidopsis.
    Nosheen Hussain, Ryan Merrit, Julia Engelhorn, Javier Antunez-Sanchez, Anjar Wibowo, David Latrasse, Travis Wrightsman, Maximillian Collenberg, Ilja Bezrukov, Hidayah Alotaibi, Elsa Carrasco, Moussa Benhamed, Detlef Weigel, Nicolae Radu Zabet, Jose Gutierrez-Marcos.
      We present iNOMe-seq, a novel method for in vivo simultaneous profiling of chromatin accessibility, nucleosome occupancy, DNA-binding protein sites, and DNA methylation in living tissues. iNOMe-seq utilizes an m5C methyltransferase to mark accessible cytosines in a GpC context, bypassing nucleosome-restricted regions. Using Arabidopsis thaliana, we demonstrate that iNOMe-seq improves chromatin accessibility quantification compared to existing methods. Furthermore, it allows for the spatial and temporal analysis of chromatin dynamics, transcription factor binding, and DNA methylation, offering insight into the role of epigenetic components in transcriptional regulation across tissues and genetic variations in natural populations.
    Keywords:   Arabidopsis ; Chromatin; Metabolic gene cluster; Nucleosome; Transcription
    DOI:  https://doi.org/10.1186/s13059-025-03760-x
  4. Nucleic Acids Res. 2025 Oct 14. pii: gkaf1025. [Epub ahead of print]53(19):
    Refined mechanism of promoter nucleosome-depleted regions resetting after replication.
    Sevil Zencir, Jatinder Kaur Gill, Françoise Stutz, Julien Soudet.
      Replication disrupts chromatin organization. Thus, the rapid resetting of nucleosome positioning is essential to maintain faithful gene expression. The initial step of this reconfiguration occurs at nucleosome-depleted regions (NDRs). While studies have elucidated the role of transcription factors (TFs) and chromatin remodelers (CRs) in vitro or in maintaining NDRs in vivo, none has addressed their in vivo function shortly after replication. Through purification of nascent chromatin in yeast, we dissected the choreography of events governing the proper positioning of the -1/+1 nucleosomes flanking promoter NDRs. Our findings reveal that CRs are the primary contributors of -1/+1 repositioning post-replication, with RSC (Remodeling the Structure of Chromatin) acting upstream of INO80. Surprisingly, while Reb1 and Abf1 TFs are not essential for NDR resetting, they are required for NDR maintenance via the promotion of H3 acetylations. Altogether, we propose a two-step model for NDR resetting in Saccharomyces cerevisiae: first, CRs alone reset promoter NDRs after replication, while a combination of TFs and CRs is required for subsequent maintenance.
    DOI:  https://doi.org/10.1093/nar/gkaf1025
  5. Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00602-1. [Epub ahead of print]
    Cell-type-specific RNA polymerase II activity maps in intact tissues provide a gateway to mammalian gene regulatory mechanisms in vivo.
    Gopal Chovatiya, Sean Y Huang, Alex B Wang, Philip Versluis, Chris K Bai, Michael DeBerardine, Yu-Ching Liao, Judhajeet Ray, Abdullah Ozer, John T Lis, Tudorita Tumbar.
      Accessing ongoing RNA polymerase II (RNA Pol II) activity in specific cell types within intact tissue is critical to reveal regulatory mechanisms of development. We developed precision run-on in cell-type-specific in vivo system followed by sequencing (PReCIS-seq), a method combining Cre-inducible GFP tagging of endogenous RNA Pol II with transcriptional run-on and GFP immunoprecipitation, to map transcriptionally engaged RNA Pol II genome-wide in targeted cell types of mouse tissues. Applied to keratinocytes within intact skin, PReCIS-seq demonstrates that transcriptionally activated functions of biological transitions generally employ both RNA Pol II promoter-recruitment and promoter-proximal pause-release mechanisms. A global RNA Pol II regulatory polarization features extreme pausing levels at cellular safeguarding vs. lineage identity genes across development and homeostasis. This polarization is associated with distinct proximal-promoter structures, distinguishing high-paused genes with restricted RNA Pol II pause-release from low-paused genes undergoing rapid RNA Pol II firing into productive elongation. PReCIS-seq also identifies active enhancers based on divergent transcription. This approach enables high-resolution, cell-type-specific analysis of RNA Pol II dynamics in intact tissues across mammalian development, homeostasis, and disease.
    Keywords:  RNA Pol II pausing in vivo; TF motifs and RNA Pol II pausing; active enhancers; cell-type-specific nascent transcriptomics; cellular safeguarding genes; epithelial lineage genes; transcription regulation
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.017
  6. Nat Cell Biol. 2025 Oct 21.
    Enhancer activation from transposable elements in extrachromosomal DNA.
    Katerina Kraft, Sedona E Murphy, Matthew G Jones, Quanming Shi, Aarohi Bhargava-Shah, Christy Luong, King L Hung, Britney J He, Rui Li, Seung Kuk Park, Michael T Montgomery, Natasha E Weiser, Yanbo Wang, Jens Luebeck, Vineet Bafna, Jef D Boeke, Paul S Mischel, Alistair N Boettiger, Howard Y Chang.
      Extrachromosomal DNA (ecDNA) drives oncogene amplification and intratumoural heterogeneity in aggressive cancers. While transposable element reactivation is common in cancer, its role on ecDNA remains unexplored. Here we map the 3D architecture of MYC-amplified ecDNA in colorectal cancer cells and identify 68 ecDNA-interacting elements-genomic loci enriched for transposable elements that are frequently integrated onto ecDNA. We focus on an L1M4a1#LINE/L1 fragment co-amplified with MYC, which functions only in the ecDNA-amplified context. Using CRISPR-CATCH, CRISPR interference and reporter assays, we confirm its presence on ecDNA, enhancer activity and essentiality for cancer cell fitness. These findings reveal that repetitive elements can be reactivated and co-opted as functional rather than inactive sequences on ecDNA, potentially driving oncogene expression and tumour evolution. Our study uncovers a mechanism by which ecDNA harnesses repetitive elements to shape cancer phenotypes, with implications for diagnosis and therapy.
    DOI:  https://doi.org/10.1038/s41556-025-01788-6
  7. Development. 2025 Oct 22. pii: dev.204770. [Epub ahead of print]
    Activity of the SWI/SNF complex is indispensable for syncytiotrophoblast formation.
    Henrieta Papuchova, Andreas Lackner, Terezia Vcelkova, Petra Tolp, Sandra Haider, Vasileios Gerakopoulos, Paulina A Latos.
      Developmental transitions are characterized by coordinated changes in lineage-specific gene expression programs and chromatin states. Yet, how these shifts in cell fate occur during placental development remains largely unknown. Here, we used human trophoblast stem cells (hTSCs), genetic depletion, and small-molecule inhibition of the SWI/SNF remodelling complex activity to address its role during syncytiotrophoblast (ST) differentiation. We found that SWI/SNF inhibition has a massive impact on gene expression, chromatin accessibility, and histone modifications, particularly H3K27ac, resulting in ST differentiation failure. We also observed cell cycle defects, indicating that SWI/SNF is required for hTSCs to exit the cell cycle, a prerequisite for ST commitment. In addition, based on motif analysis of SWI/SNF target regions, we genetically tested several early ST candidate transcription factors. While GCM1, CEBPB, and TBX3 are vital for ST differentiation, only GCM1 is sufficient to induce ST fate. Together, our results demonstrate that SWI/SNF activity is essential for lineage specification during placental development.
    Keywords:  Placenta; SWI/SNF; Trophoblast stem cells
    DOI:  https://doi.org/10.1242/dev.204770
  8. Cell Stem Cell. 2025 Oct 20. pii: S1934-5909(25)00340-6. [Epub ahead of print]
    EZHIP restricts noncanonical PRC2 binding and regulates H3K27me3 intergenerational inheritance and reprogramming.
    Yitian Zeng, Feng Kong, Zihan Xu, Xukun Lu, Qian Li, Bofeng Liu, Shu Liu, Lijun Dong, Ling Liu, Wenying Wang, Bing Zhu, Wei Xie.
      In mice, the repressive histone mark H3K27me3 undergoes both region-specific inheritance and erasure during the parental-to-embryonic transition, with the underlying mechanisms poorly understood. Here, we show that PRC2, which catalyzes H3K27me3, binds both classic Polycomb targets and noncanonical H3K27me3 domains in growing oocytes but dissociates from chromatin in fully grown oocytes. After fertilization, PRC2 rebinds noncanonical H3K27me3 domains before relocating to Polycomb targets in blastocysts. Interestingly, the binding and activity of PRC2 are restricted by a maternal inhibitory factor, EZH inhibitory protein (EZHIP), which co-binds with PRC2. Upon knockout of Ezhip, hyperactive PRC2 promiscuously deposits H3K27me3 genome-wide. This overwrites H3K27me3 memories at noncanonical imprinted genes and paradoxically causes derepression of H3K27me3 targets, defective X chromosome inactivation, and diluted chromatin PRC2. H3K27me3 restoration at Polycomb targets after implantation is also attenuated, accompanied by sub-lethality. These data unveil principles of epigenetic inheritance that both insufficient and excessive heterochromatic marks cause loss of epigenetic memories and repression.
    Keywords:  EZHIP; H3K27me3; Polycomb regulation; early embryo; epigenetic memory; epigenetic reprogramming; intergenerational inheritance; noncanonical imprinting
    DOI:  https://doi.org/10.1016/j.stem.2025.09.009
  9. Nat Struct Mol Biol. 2025 Oct 23.
    Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification.
    Rebecca M Starble, Eric G Sun, Rana Gbyli, Jonathan Radda, Jiuwei Lu, Tyler B Jensen, Ning Sun, Nelli Khudaverdyan, Ting Zhao, Bomiao Hu, Mary Ann Melnick, Shuai Zhao, Nitin Roper, Gang Greg Wang, Alan J Tackett, Yinsheng Wang, Jikui Song, Katerina Politi, Siyuan Wang, Andrew Z Xiao.
      In mammalian cells, gene copy number is controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, increasing the copy number and expression of tumor-promoting genes and thus promoting cancer progression. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification is frequent. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the underlying mechanisms are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identify a global chromatin-priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading and inter-TAD interactions, which occur before the onset of oncogene amplification. Furthermore, we show that METTL7A, reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. METTL7A appears to remodel the chromatin landscape prior to large-scale copy number gains. Although METTL7A depletion exerts little phenotypical effects on drug-naive cells, its depletion prevents the formation and maintenance of TKI resistant-clones, showcasing its role as cells become resistant. In summary, we unveil a mechanism required for the acquisition of TKI resistance regulated by an unexpected chromatin function of METTL7A.
    DOI:  https://doi.org/10.1038/s41594-025-01685-4
  10. Sci Rep. 2025 Oct 23. 15(1): 37129
    Characterization of core promoter activation by the Drosophila insulator-binding protein BEAF.
    Sunday Negedu, Elizabeth J Vidrine, Craig M Hart.
      Housekeeping and regulated genes have distinct core promoter motif usage and architecture. The Boundary Element-Associated Factor of 32 kDa, BEAF, was identified as a chromatin domain insulator protein that affects chromatin structure and plays a role in insulator function. Genome-wide mapping found that it usually binds near transcription start sites of housekeeping genes found at topologically associating domain (TAD) boundaries, suggesting roles in both insulator function and gene activation. This was substantiated when it was found to activate the RpS12 and aurA promoters, and that BEAF-dependent promoter activation could be separated from BEAF-dependent insulator activity. Here, we use luciferase assays after transient transfection of Drosophila S2 cells to show that adding an upstream BEAF binding site leads to activation of housekeeping promoters without showing a preference for particular housekeeping core promoter motifs, and also activates core promoters lacking motifs or with only an Inr. Regulated core promoters with a TATA box or with an Inr plus MTE or DPE or both are not activated. Activation by BEAF has a weak negative correlation with promoter basal activity. We additionally show that BEAF activates promoters synergistically with DRE or Motif 1 housekeeping promoter motifs. This establishes BEAF as an activator for a large set of promoters.
    Keywords:  BEAF; Chromatin domain insulators; Core promoters; Drosophila; Gene regulation; Transcription activation
    DOI:  https://doi.org/10.1038/s41598-025-21036-z
  11. Cell Rep. 2025 Oct 20. pii: S2211-1247(25)01198-2. [Epub ahead of print]44(11): 116427
    Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.
    Jessica King, Stephen S Gisselbrecht, Julie-Alexia Dias, Raehoon Jeong, Elisabeth Rothman, Martha L Bulyk.
      Recognition of specific DNA sequences by transcription factors (TFs) is a key step in transcriptional control of gene expression. While most forkhead (FH) TFs bind either an FKH (RYAAAYA) or an FHL (GACGC) recognition motif, some FHs can bind both motifs. Mechanisms that control whether an FH is monospecific vs. bispecific have remained unknown. Screening a library of 12 reference FH proteins, 61 naturally occurring missense variants including clinical variants, and 22 designed mutant FHs for DNA-binding activity using universal ("all 10-mer") protein-binding microarrays revealed non-DNA-contacting residues that control mono- vs. bispecificity. Variation in non-DNA-contacting amino acid residues of TFs is associated with human traits and may play a role in the evolution of TF DNA-binding activities and gene regulatory networks.
    Keywords:  CP: Molecular biology; DNA binding activity; bispecificity; coding variants; forkhead; protein-binding microarrays; rare variants; specificity determinants; transcription factor; transcription factor-DNA recognition
    DOI:  https://doi.org/10.1016/j.celrep.2025.116427
  12. Elife. 2025 Oct 22. pii: RP102784. [Epub ahead of print]14
    Chromatin activity of IκBα mediates the exit from naïve pluripotency.
    Luis G Palma, Daniel Alvarez-Villanueva, Maria Maqueda, Mercedes Barrero, Arnau Iglesias, Joan Bertran, Damiana Alvarez, Carlos A Garcia-Prieto, Cecilia Ballare, Virginia Rodriguez-Cortez, Clara Bueno, August Vidal, Alberto Villanueva, Pablo Menendez, Gregoire Stik, Luciano Di Croce, Bernhard Payer, Manel Esteller, Lluis Espinosa, Anna Bigas.
      Maintenance of pluripotency is a multifactorial process in which NF-κB is a negative regulator. Our previous work identified a chromatin role for IκBα, the master regulator of NF-κB signaling, that is critical for the proper regulation of various tissue stem cells. Here, we found that IκBα accumulates specifically in the chromatin fraction of mouse pluripotent stem cells. IκBα depletion does not affect NF-kB-dependent transcription, but causes a profound epigenetic rewiring in pluripotent stem cells, including alterations in H3K27me3, a histone mark catalyzed by Polycomb repression complex 2. Chromatin changes induced by IκBα depletion affect a subset of pluripotency genes and are associated with altered gene transcription. At the cellular level, IκBα-deficient embryonic stem cells are arrested in a naive pluripotency state when cultured in serum/LIF conditions and fail to exit pluripotency under differentiation conditions. By constructing separation-of-function mutants, we show that the effects of IκBα in regulating stem cell pluripotency are NF-κB-independent, but mainly rely on its chromatin-related function. Taken together, our results reveal a novel mechanism by which IκBα participates in the regulation of the pluripotent state of mouse embryonic stem cells and shed light on the interplay between inflammatory signals and the regulation of pluripotency.
    Keywords:  NFKB; NFKBIA; PRC2; embryonic stem cells; ikappabalpha; mouse; pluripotency exit; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.102784
  13. Mol Cell. 2025 Oct 17. pii: S1097-2765(25)00785-3. [Epub ahead of print]
    Sequential verification of transcription by Integrator and Restrictor.
    Chris Estell, Krystian Łazowski, Joshua D Eaton, Steven West.
      The decision between productive elongation and premature termination of promoter-proximal RNA polymerase II (RNAPII) is fundamental to metazoan gene regulation. Integrator and Restrictor complexes are implicated in promoter-proximal termination, but why metazoans utilize two complexes and how they are coordinated remains unknown. Here, we show that Integrator and Restrictor act sequentially to monitor distinct stages of transcription. Integrator predominantly engages with promoter-proximally paused RNAPII to trigger premature termination, which is prevented by cyclin-dependent kinase 7/9 activity. After pause release, RNAPII enters a "restriction zone"-universally imposed by Restrictor. Unproductive RNAPII terminates within this zone, while progression through it is promoted by U1 small nuclear ribonucleoprotein particles (snRNPs), which antagonize Integrator and Restrictor in a U1-70K-dependent manner. These findings reveal the principles of a sequential verification mechanism governing the balance between productive and attenuated transcription, rationalizing the necessity of Integrator and Restrictor complexes in metazoans.
    Keywords:  Integrator; RNA exosome; RNA polymerase II; Restrictor; U1 snRNA; ZC3H4; transcription; transcriptional elongation; transcriptional termination
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.025
  14. Nat Methods. 2025 Oct 22.
    scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution.
    Johannes C Hingerl, Laura D Martens, Alexander Karollus, Trevor Manz, Jason D Buenrostro, Fabian J Theis, Julien Gagneur.
      Understanding how regulatory sequences shape gene expression across individual cells is a fundamental challenge in genomics. Joint RNA sequencing and epigenomic profiling provides opportunities to build models capturing sequence determinants across steps of gene expression. However, current models, developed primarily for bulk omics data, fail to capture the cellular heterogeneity and dynamic processes revealed by single-cell multimodal technologies. Here, we introduce scooby, a framework to model genomic profiles of single-cell RNA-sequencing coverage and single-cell assay for transposase-accessible chromatin using sequencing insertions from sequence at single-cell resolution. For this, we leverage the pretrained multiomics profile predictor Borzoi and equip it with a cell-specific decoder. Scooby recapitulates cell-specific expression levels of held-out genes and identifies regulators and their putative target genes. Moreover, scooby allows resolving single-cell effects of bulk expression quantitative trait loci and delineating their impact on chromatin accessibility and gene expression. We anticipate scooby to aid unraveling the complexities of gene regulation at the resolution of individual cells.
    DOI:  https://doi.org/10.1038/s41592-025-02854-5
  15. Nat Chem Biol. 2025 Oct 23.
    MED1 IDR deacetylation controls stress responsive genes through RNA Pol II recruitment.
    Ran Lin, Yan Mo, Douglas Barrows, Wenbin Mei, Takashi Onikubo, Jianfeng Sun, Zhiguo Zhang, Effie Apostolou, Sohail F Tavazoie, Robert G Roeder.
      Cells fine-tune gene expression in response to cellular stress, a process critical for tumorigenesis. However, mechanisms governing stress-responsive transcription remain incompletely understood. This study shows that the MED1 subunit of the Mediator coactivator complex is acetylated in its intrinsically disordered region (IDR). Under stress, SIRT1 associates with the super elongation complex to deacetylate MED1 in promoter-proximal regions. The deacetylated (or acetylation-defective mutant) MED1 amplified stress-activated cytoprotective genes and rescued stress-suppressed growth-supportive genes in estrogen-receptor-positive breast cancer (ER+ BC) cells. Mechanistically, deacetylated MED1 promotes chromatin incorporation of RNA polymerase II (Pol II) through IDR-mediated interactions. Functionally, ER+ BC cells with deacetylated MED1 exhibit faster growth and enhanced stress resistance in culture and in an orthotopic mouse model. These findings advance our understanding of Pol II regulation under cellular stress and potentially suggest therapeutic strategies targeting oncogenic transcription driven by MED1 and Mediator.
    DOI:  https://doi.org/10.1038/s41589-025-02035-7
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