bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–08–17
seventeen papers selected by
Connor Rogerson, University of Cambridge
  1. Establishment of chromatin architecture interplays with embryo hypertranscription.
  2. HMGB1 deforms nucleosomal DNA to generate a dynamic chromatin environment counteracting the effects of linker histone.
  3. RNA Pol II-based regulations of chromosome folding.
  4. Defining transcription factor nucleosome binding with Pioneer-seq.
  5. Single-stranded DNA-binding proteins are essential components of the architectural LDB1 protein complex.
  6. REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate.
  7. Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions.
  8. Genome-wide investigation of transcription factor occupancy and dynamics using cFOOT-seq.
  9. YAP charge patterning mediates signal integration through transcriptional co-condensates.
  10. Intergenic accumulation of RNAPII maintains the potential for swift transcriptional restart upon release from quiescence.
  11. Plants repress ROS1 expression to attenuate heat-induced transposon burst.
  12. Chromatin accessibility analysis reveals functional cis-regulatory regions related to fruit development and domestication in tomato.
  13. SMAD1/5-Mediated Recruitment of the Histone Demethylase KDM1A Controls Cell Fate Programs in Embryonic Stem Cells.
  14. SETD6 mediates selective interaction and genomic occupancy of BRD4 and MITF in melanoma cells.
  15. Gene regulatory logic of the interferon-β enhancer is characterized by two selectively deployed modes of transcription factor synergy.
  16. UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells.
  17. MyoD is essential in rhabdomyosarcoma by promoting survival through differentiation and CYLD.
  1. Nature. 2025 Aug 13.
    Establishment of chromatin architecture interplays with embryo hypertranscription.
    Guang Yu, Kai Xu, Weikun Xia, Ke Zhang, Qianhua Xu, Lijia Li, Zili Lin, Ling Liu, Bofeng Liu, Zhenhai Du, Xia Chen, Qiang Fan, Fangnong Lai, Wenying Wang, Lijuan Wang, Feng Kong, Chao Wang, Haiqiang Dai, Huili Wang, Wei Xie.
      After fertilization, early embryos undergo dissolution of conventional chromatin organization, including topologically associating domains (TADs)1,2. Zygotic genome activation then commences amid unusually slow de novo establishment of three-dimensional chromatin architecture2. How chromatin organization is established and how it interplays with transcription in early mammalian embryos remain elusive. Here we show that CTCF occupies chromatin throughout mouse early development. By contrast, cohesin poorly binds chromatin in one-cell embryos, coinciding with TAD dissolution. Cohesin binding then progressively increases from two- to eight-cell embryos, accompanying TAD establishment. Unexpectedly, strong 'genic cohesin islands' (GCIs) emerge across gene bodies of active genes in this period. GCI genes enrich for cell identity and regulatory genes, display broad H3K4me3 at promoters, and exhibit strong binding of transcription factors and the cohesin loader NIPBL at nearby enhancers. We show that transcription is hyperactive in two- to eight-cell embryos and is required for GCI formation. Conversely, induced transcription can also create GCIs. Finally, GCIs can function as insulation boundaries and form contact domains with nearby CTCF sites, enhancing both the transcription levels and stability of GCI genes. These data reveal a hypertranscription state in early embryos that both shapes and is fostered by the three-dimensional genome organization, revealing an intimate interplay between chromatin structure and transcription.
    DOI:  https://doi.org/10.1038/s41586-025-09400-5
  2. Sci Adv. 2025 Aug 15. 11(33): eads4473
    HMGB1 deforms nucleosomal DNA to generate a dynamic chromatin environment counteracting the effects of linker histone.
    Hayden S Saunders, Un Seng Chio, Camille M Moore, Vijay Ramani, Yifan Cheng, Geeta J Narlikar.
      The essential architectural protein HMGB1 increases accessibility of nucleosomal DNA and counteracts the effects of linker histone H1. However, HMGB1 is less abundant than H1 and binds nucleosomes more weakly, raising the question of how it competes with H1. Here, we find that HMGB1 increases nucleosomal DNA accessibility without displacing H1. HMGB1 also increases the dynamics of condensed, H1-bound chromatin. Unexpectedly, cryo-electron microscopy structures show HMGB1 bound at internal locations on nucleosomes and local DNA distortion. These sites are away from where H1 binds, explaining how HMGB1 and H1 can co-occupy a nucleosome. Our findings suggest a model where HMGB1 counteracts the effects of H1 by distorting nucleosomal DNA and disrupting interactions of the H1 carboxyl-terminal tail with DNA. Compared to mutually exclusive binding, co-occupancy by HMGB1 and H1 allows greater diversity in dynamic chromatin states. More generally, these results explain how architectural proteins acting at the nucleosome scale can have large effects on chromatin dynamics at the mesoscale.
    DOI:  https://doi.org/10.1126/sciadv.ads4473
  3. Cell Genom. 2025 Aug 06. pii: S2666-979X(25)00226-5. [Epub ahead of print] 100970
    RNA Pol II-based regulations of chromosome folding.
    Christophe Chapard, Nathalie Bastié, Axel Cournac, Laura Chaptal, Henri Mboumba, Sophie Queille, Agnes Thierry, Olivier Gadal, Armelle Lengronne, Romain Koszul, Frédéric Beckouët.
      The spatial organization of eukaryotic genomes and its dynamics are of functional importance for gene expression, DNA replication, and segregation. Structural maintenance of chromosome (SMC) complexes are essential instruments of chromosome folding, enabling long-distance intra-chromatid DNA loops. The interplay between these processes is complex. For instance, cohesin, in addition to tethering sister chromatids, dynamically regulates gene expression in mammals by promoting interactions between distal regulatory elements and promoters, whereas transcription itself affects genome folding in many ways. Here, we comprehensively dissect the relative contributions of transcription and cohesin complexes, as well as their interplay, to yeast S. cerevisiae genome organization. In particular, we show that transcription (1) is not a motor required to push cohesin during DNA loop expansion, (2) specifically induces the appearance of DNA loops independently of SMC complexes, and (3) interferes with cohesin-mediated DNA loop expansion during their establishment.
    Keywords:  DNA domain; DNA loop; RNA pol II transcription; S. cerevisiae; SMC; cohesin; genome organization
    DOI:  https://doi.org/10.1016/j.xgen.2025.100970
  4. PLoS Genet. 2025 Aug 14. 21(8): e1011813
    Defining transcription factor nucleosome binding with Pioneer-seq.
    Maria Tsompana, Patrick D Wilson, Vijaya Murugaiyan, Christopher R Handelmann, Michael J Buck.
      Gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. To comprehensively examine TF nucleosome binding, we developed Pioneer-Seq. In Pioneer-seq a library of thousands of nucleosomes are formed from sequences containing a TF binding site (TFBS) variant in all possible nucleosome orientations and within the linker regions. Pioneer-seq has the unique ability to simultaneously examine nucleosomes created with various nucleosome positioning sequences and examine binding to in vivo targeted nucleosomes (ITNs). Pioneer-seq can be applied to address various mechanistic models for TF-nucleosome binding directly and can be used to uncover inherent TF-interaction differences. To demonstrate Pioneer-seq, we examined nucleosome binding by OCT4, SOX2, KLF4, and c-MYC. Our results demonstrate that all studied TFs can bind at nucleosome edges and nucleosome sequence is the primary factor regulating TF binding. In addition, KLF4 can bind to a non-canonical TFBS located 20 bp from the nucleosome dyad. Examination of ITNs showed binding differences between the TFs, with KLF4 and SOX2 binding more often near nucleosome centers. Overall, our results demonstrate differences in how TF recognizes their TFBS within a nucleosome and begins to define the mechanistic requirements for pioneer factor binding.
    DOI:  https://doi.org/10.1371/journal.pgen.1011813
  5. Mol Cell. 2025 Aug 07. pii: S1097-2765(25)00613-6. [Epub ahead of print]
    Single-stranded DNA-binding proteins are essential components of the architectural LDB1 protein complex.
    Xiaokang Wang, Nicholas G Aboreden, Ying Cai, Jessica C Lam, Kate A Henderson, Jiaqi Xiang, Belinda M Giardine, Ross C Hardison, Cheryl A Keller, Lalitha Nagarajan, Stephen J Brandt, Gerd A Blobel.
      Transcriptional enhancers are brought into proximity with promoters via chromatin looping. The architectural transcription cofactor LDB1 facilitates spatial connectivity among enhancers and promoters, but whether this occurs through simple dimerization or requires heterotypic protein assemblies is unknown. Here, we investigated the role of single-stranded DNA-binding proteins (SSBPs) in regulating LDB1-mediated chromatin looping and transcription. SSBP2, SSBP3, and SSBP4 colocalize with LDB1 genome wide. Among these, only SSBP3 is essential for murine erythroid cell viability, LDB1 function, and transcription. LDB1, but not single-stranded DNA, is the predominant genome-wide tether of SSBP3 to chromatin. SSBP3 depletion in SSBP2/4 knockout cells globally weakened LDB1-dependent chromatin loops and lowered nascent transcription without impacting LDB1's chromatin binding. Chromatin tethering experiments revealed that SSBP3 and LDB1 mutually depend on each other to form looped contacts. SSBP3 stabilizes LDB1 dimerization in vitro, providing a possible mechanism. SSBPs emerge as key functional components of the architectural LDB1 complex.
    Keywords:  LDB1; SSBP2; SSBP3; SSBP4; chromatin looping; enhancer-promoter interaction; single-stranded DNA-binding protein; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.012
  6. Nat Commun. 2025 Aug 12. 16(1): 7487
    REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate.
    Korin Sahinyan, Darren M Blackburn, Marie-Michelle Simon, Felicia Lazure, Tony Kwan, David H Wilson, Maryam Vahidyeganeh, Nawal Alsadi, Julia von Maltzahn, Yasuhiro Yamada, Arezu Jahani-Asl, Guillaume Bourque, Michael A Rudnicki, Vahab D Soleimani.
      Cell fate and identity require timely activation of lineage-specific and concomitant repression of alternate-lineage genes. How this process is epigenetically encoded remains largely unknown. In skeletal muscle stem cells, the myogenic regulatory factors are well-established drivers of muscle gene activation but less is known about how non-muscle gene repression is achieved. Here, we show that the master epigenetic regulator, Repressor Element 1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a key regulator of this process. We show that many non-lineage genes retain permissive chromatin state but are actively repressed by REST. Loss of functional REST in muscle stem cells and progenitors disrupts muscle specific epigenetic and transcriptional signatures, impairs differentiation, and triggers apoptosis in progenitor cells, leading to depletion of the stem cell pool. Consequently, REST-deficient skeletal muscle exhibits impaired regeneration and reduced myofiber growth postnatally. Collectively, our data suggests that REST plays a key role in safeguarding muscle stem cell identity by repressing multiple non-muscle lineage and developmentally regulated genes in adult mice.
    DOI:  https://doi.org/10.1038/s41467-025-62758-y
  7. Nat Commun. 2025 Aug 14. 16(1): 7566
    Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions.
    Yuan-Hung Lo, Hudson T Horn, Mo-Fan Huang, Wei-Chieh Yu, Chia-Mei Young, Qing Liu, Madeline Tomaske, Martina Towers, Antonia Dominguez, Michael C Bassik, Dung-Fang Lee, Lei S Qi, Jonathan S Weissman, Jin Chen, Calvin J Kuo.
      Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the level of individual cells and uncover an unexpected link between fucosylation and cisplatin sensitivity. We identify TAF6L as a regulator of cell recovery from cisplatin-induced cytotoxicity. These results highlight the utility of human organoid models for dissecting gene-drug interactions and offer insights into therapeutic vulnerabilities in gastric cancer.
    DOI:  https://doi.org/10.1038/s41467-025-62818-3
  8. Protein Cell. 2025 Aug 04. pii: pwaf071. [Epub ahead of print]
    Genome-wide investigation of transcription factor occupancy and dynamics using cFOOT-seq.
    Heng Wang, Ang Wu, Meng-Chen Yang, Di Zhou, Xiyang Chen, Zhifei Shi, Yiqun Zhang, Yu-Xin Liu, Kai Chen, Xiaosong Wang, Xiao-Fang Cheng, Baodan He, Yutao Fu, Lan Kang, Yujun Hou, Kun Chen, Shan Bian, Juan Tang, Jianhuang Xue, Chenfei Wang, Xiaoyu Liu, Jiejun Shi, Shaorong Gao, Jia-Min Zhang.
      Gene regulation relies on the precise binding of transcription factors (TFs) at regulatory elements, but simultaneously detecting hundreds of TFs on chromatin is challenging. We developed cFOOT-seq, a cytosine deaminase-based TF footprinting assay, for high-resolution, quantitative genome-wide assessment of TF binding in both open and closed chromatin regions, even with small cell numbers. By utilizing the dsDNA deaminase SsdAtox, cFOOT-seq converts accessible cytosines to uracil while preserving genomic integrity, making it compatible with techniques like ATAC-seq for sensitive and cost-effective detection of TF occupancy at single-molecule and single-cell level. Our approach enables the delineation of TF footprints, quantification of occupancy, and examination of chromatin influences on TF binding. Notably, cFOOT-seq, combined with FootTrack analysis, enables de novo prediction of TF binding sites and tracking of TF occupancy dynamics. We demonstrate its application in capturing cell type-specific TFs, analyzing TF dynamics during reprogramming, and revealing TF dependencies on chromatin remodelers. Overall, cFOOT-seq represents a robust approach for investigating the genome-wide dynamics of TF occupancy and elucidating the cis-regulatory architecture underlying gene regulation.
    Keywords:  BRM014; TF footprint; TF occupancy; TF organization; chromatin accessibility; chromatin landscape; chromatin remodeling; gene regulation; nucleosome position; transcription factor
    DOI:  https://doi.org/10.1093/procel/pwaf071
  9. Nat Commun. 2025 Aug 12. 16(1): 7454
    YAP charge patterning mediates signal integration through transcriptional co-condensates.
    Kirstin Meyer, Klaus Yserentant, Rasmi Cheloor-Kovilakam, Kiersten M Ruff, Chan-I Chung, Xiaokun Shu, Bo Huang, Orion D Weiner.
      Transcription factor dynamics are used to selectively engage gene regulatory programs. Biomolecular condensates have emerged as an attractive signaling module in this process, but the underlying mechanisms are not well-understood. Here, we probe the molecular basis of YAP signal integration through transcriptional condensates. Leveraging light-sheet single-molecule imaging and synthetic condensates, we demonstrate charge-mediated co-condensation of the transcriptional regulators YAP and Mediator into transcriptionally active condensates in stem cells. Intrinsically disordered region sequence analysis and YAP protein engineering demonstrate that the signaling specificity of YAP is established, in part, through complementary electrostatic interactions between negatively charged blocks within YAP and positively charged blocks within Mediator. YAP/Mediator co-condensation is counteracted by negative feedback from transcription, driving an adaptive transcriptional response that is well-suited for decoding dynamic inputs. Our work reveals a molecular framework for YAP condensate formation and sheds light on the function of YAP condensates for emergent gene regulatory behavior.
    DOI:  https://doi.org/10.1038/s41467-025-62157-3
  10. Genome Res. 2025 Aug 12. pii: gr.279874.124. [Epub ahead of print]
    Intergenic accumulation of RNAPII maintains the potential for swift transcriptional restart upon release from quiescence.
    Manuela Baquero Pérez, Gertjan Laenen, Isabelle Loïodice, Mickaël Garnier, Ugo Szachnowski, Antonin Morillon, Myriam Ruault, Angela Taddei.
      Quiescent cells (Q) are seemingly inactive, developmentally arrested cells, whose universal characteristic is the ability to promptly reenter the cell cycle upon sensing of external cues. Q cells are responsive to the environment and flexible enough to adapt to available resources. In budding yeast, quiescent nuclear features are drastically distinct from those observed in nutrient replete conditions: the nuclear volume is reduced, the telomeres relocate from the nuclear periphery to the center of the nucleus into a hypercluster, chromatin is found in a compacted, hypoacetylated state, and transcription is globally shutdown. Yet, Q cells can restart transcription within minutes of refeeding. Here, we follow the global decrease of transcription in sorted, developing Q populations, and its reactivation upon release. We find that transcription and telomere clustering dynamics in and out of quiescence are independent events. We report a genome-wide redistribution of the transcription machinery as cells progress into quiescence. Although most genes are shut down, 3% of coding genes remain active. Furthermore, RNAPII accumulates at one third of gene promoters. The corresponding genes are highly enriched among those showing a high level of transcription and high frequency of expression in individual cells, shortly after cells are refed, as monitored by single-cell RNA-seq. Our results point toward a role for quiescent-specific RNAPII distribution to ensure a rapid and robust transcriptional response upon return to growth.
    Keywords:  Nuclear organization; Quiescence; RNA Pol II; return to growth; single cell RNA-Seq
    DOI:  https://doi.org/10.1101/gr.279874.124
  11. Nat Plants. 2025 Aug 11.
    Plants repress ROS1 expression to attenuate heat-induced transposon burst.
    Lingjiao Fan, Yuqing Jing, Xinyu Liu, Wenxin Zhang, Yingjie Mi, Linhua Sun, Liu-Min Fan, Weiqiang Qian.
      The active DNA demethylase Repressor of Silencing 1 (ROS1) regulates genomic DNA methylation patterns during plant development. ROS1 expression is promoted by DNA methylation within its promoter region. However, the mechanisms and biological significance of ROS1 regulation under abiotic stresses remain elusive. Here we show that heat stress reduces DNA methylation in the ROS1 promoter to suppress its expression. Under normal conditions, SUVH1 and SUVH3 bind methylated ROS1 promoter regions, inhibiting chromatin interactions around the ROS1 locus; heat stress triggers their dissociation, enabling chromatin loop formation to suppress ROS1 transcription. Transgenic plants with exogenous ROS1 maintain high expression levels during heat stress, causing transposable element hypomethylation and enhanced transcription and transgenerational transposition of the heat-activated retrotransposon ONSEN. We propose that heat-induced suppression of ROS1 transcription, which is conserved across plant species, serves as a brake system to limit transposable element activation, thereby safeguarding genome stability.
    DOI:  https://doi.org/10.1038/s41477-025-02076-9
  12. Plant J. 2025 Aug;123(3): e70416
    Chromatin accessibility analysis reveals functional cis-regulatory regions related to fruit development and domestication in tomato.
    Ying-Juan Cheng, Yu Zhang, Jiao Yu, Xiang-Ru Meng, Zhong-Yuan Chang, Fang-Ling Jiang, Zhen Wu, Ying-Ying Zhang, Jia-Yu Xue, Tian-Qi Zhang.
      Non-coding DNA sequences harbor vast regulatory programs that ensure the precise spatiotemporal control of gene expression, which is essential for proper plant development and trait formation. Chromatin accessibility analysis could identify functional DNA regions within the extensive non-coding sequences and infer regulatory elements, serving as a crucial approach to unravel the mysteries of non-coding DNA sequences. Tomato fruit, a fleshy organ, provides a special system for studying fruit development and trait formation. However, the role of cis-accessible chromatin regions (cis-ACRs) during tomato fruit development, particularly in comparison with protein-coding DNA sequences, remains poorly understood. Here, we used ATAC-seq to define the landscape of cis-ACRs during fruit development and domestication in tomato. Temporal differential analysis revealed the dynamic opening and closing of cis-ACRs during fruit development. Comparative analysis of cis-ACRs between cultivated and wild tomatoes highlighted their significant contributions to fruit domestication. Combining analysis with genomic structural variations (SVs) suggested that SVs are likely a key factor in the formation of specific accessible cis-ACRs in cultivated tomatoes. Moreover, using gene editing, we identified a functional cis-ACR within the intron of the MBP3 gene that regulates fruit development and size traits. Overall, our findings provide a comprehensive perspective on the roles of cis-ACRs in tomato fruit development and domestication.
    Keywords:  accessible chromatin region; cis‐regulatory region; fruit development; non‐coding DNA sequences; tomato
    DOI:  https://doi.org/10.1111/tpj.70416
  13. J Biol Chem. 2025 Aug 12. pii: S0021-9258(25)02442-1. [Epub ahead of print] 110591
    SMAD1/5-Mediated Recruitment of the Histone Demethylase KDM1A Controls Cell Fate Programs in Embryonic Stem Cells.
    Masato Morikawa, Daizo Koinuma, Hiroaki Sakai, Yusuke Kanda, Keiko Yuki, Koji Okamoto, Kohei Miyazono.
      Bone morphogenetic proteins (BMPs) play diverse roles in mouse embryonic stem cell (mESC) biology. Recent studies suggest that BMPs induce multiple cell fates and enhance mESC heterogeneity by cross-activating multiple signaling pathways. Although BMPs primarily signal through SMAD1 and SMAD5 in mESCs, their roles remain incompletely defined. Here, we investigated the SMAD signaling pathway using Smad1/5-deficient (S1/5 dKO) mESCs. While SMAD1/5 depletion may influence mESC heterogeneity, single-cell RNA sequencing (scRNA-seq) revealed only minor differences between S1/5 dKO and wild-type cells, suggesting that the observed changes are not due to altered cell states. Chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that SMAD1/5 recruit the histone demethylase KDM1A/LSD1 to specific genomic regions, where it removes H3K4me1/2 marks associated with enhancers. scRNA-seq of Kdm1a-deficient mESCs during embryoid body differentiation further supported this mechanism. This study reveals a transcriptional repression mechanism of SMAD1/5, involving KDM1A-dependent H3K4me1/2 depletion and the regulation of cell-type-specific gene expression programs.
    Keywords:  SMAD transcription factor; bone morphogenetic protein (BMP); embryonic stem cell (ESC); histone demethylase; transcription enhancer
    DOI:  https://doi.org/10.1016/j.jbc.2025.110591
  14. NAR Cancer. 2025 Sep;7(3): zcaf023
    SETD6 mediates selective interaction and genomic occupancy of BRD4 and MITF in melanoma cells.
    Tzofit Elbaz Biton, Michal Feldman, Tomer Davidy, Nili Tickotsky Moskovitz, Liron Levin, Daniel Sevilla, Colin R Goding, Emily Bernstein, Dan Levy.
      Aberrant transcriptional programs mediate malignant transformation of melanoma, the most aggressive form of skin cancer. The lysine methyltransferase SETD6 has been implicated in regulating transcription, cell adhesion, migration, and other processes in various cancers; however its role in melanoma remains unexplored. We recently reported that SETD6 monomethylates the BRD4 at K99 to selectively regulate transcription of genes involved in mRNA (messenger RNA) translation. Here, we observed that BRD4 methylation at K99 by SETD6 occurs in melanoma cells. Knockout of SETD6 or a point mutation at BRD4-K99 disrupts BRD4 genomic occupancy. In addition, we show that SETD6 interacts with MITF, a master transcription factor in melanocytes and melanoma, and influences the genomic distribution of MITF. Mechanistically, we uncover a novel chromatin-localized interaction between BRD4 and MITF in melanoma. Our data suggest that BRD4 binds MITF in melanoma cells and that this interaction is dependent on both SETD6-mediated methylation of BRD4 and MITF acetylation. This chromatin complex plays a pivotal role in selective recruitment of BRD4 and MITF to different genomic loci in melanoma cells.
    DOI:  https://doi.org/10.1093/narcan/zcaf023
  15. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2502800122
    Gene regulatory logic of the interferon-β enhancer is characterized by two selectively deployed modes of transcription factor synergy.
    Allison Schiffman, Zhang Cheng, Diana Ourthiague, Alexander Hoffmann.
      Type I interferon IFNβ is a key immune response cytokine, and when its expression is dysregulated, it causes disease. The regulation of IFNβ enhancer has been a touchpoint of mammalian gene control research since the discovery of functional synergy between two stimulus-responsive transcription factors (TFs), nuclear factor kappa B (NFκB) and interferon regulatory factors (IRF). However, subsequent gene knockout studies revealed that in some conditions either NFκB or IRF activation can be dispensable, leaving the precise regulatory logic of IFNβ transcription an open question. Here, we developed a series of quantitative enhancer states models of IFNβ expression control and evaluated them with stimulus-response data from TF knockouts. Of these, our analysis reveals that two modes of TF synergy account for the available data and neither is based on binding cooperativity. The first involves two adjacent IRF dimers, with a sigmoidal binding curve at the distal site rendering it ultrasensitive and restricting it to conditions of high IRF activity upon viral infection. The second is driven by the proximal site, which has high affinity and synergizes with NFκB to enable about half-maximal expression in response to bacterial exposure. Its accessibility is controlled by the competitive repressor p50:p50, which prevents basal IRF from binding, such that NFκB-only stimuli do not induce IFNβ expression and may allow for prior-exposure-dependent tuning. The model explains how the regulatory logic of the IFNβ enhancer ensures invariant IFNβ expression in response to viral exposure, while providing tunable, context-dependent expression in response to bacterial exposure.
    Keywords:  NFκB; boolean logic gates; interferon regulatory factors (IRF); interferon-β; thermodynamic state ensemble models
    DOI:  https://doi.org/10.1073/pnas.2502800122
  16. Nat Commun. 2025 Aug 09. 16(1): 7350
    UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells.
    Ambre Bender, Marion Morel, Michael Dumas, Muriel Klopfenstein, Naël Osmani, Maxim V C Greenberg, Déborah Bourc'his, Norbert B Ghyselinck, Michael Weber.
      In mammals, primordial germ cells (PGCs) undergo global erasure of DNA methylation with delayed demethylation of germline genes and selective retention of DNA methylation at evolutionarily young retrotransposons. However, the molecular mechanisms of persistent DNA methylation in PGCs remain unclear. Here we report that resistance to DNA methylation reprogramming in PGCs requires UHRF2, the paralog of the DNMT1 cofactor UHRF1. PGCs from Uhrf2 knock-out mice show loss of retrotransposon DNA methylation, while DNA methylation is unaffected in somatic cells. This is not associated with changes in the expression of retrotransposons in E13.5 PGCs, indicating that other mechanisms compensate for retrotransposon control at this stage. Furthermore, Uhrf2-deficient PGCs show precocious demethylation of germline genes and overexpress meiotic genes in females. Subsequently, Uhrf2-deficient mice show impaired oocyte development and female-specific reduced fertility, as well as incomplete remethylation of retrotransposons during spermatogenesis. These findings reveal a crucial function for the UHRF1 paralog UHRF2 in controlling DNA methylation in the germline.
    DOI:  https://doi.org/10.1038/s41467-025-61954-0
  17. iScience. 2025 Aug 15. 28(8): 113149
    MyoD is essential in rhabdomyosarcoma by promoting survival through differentiation and CYLD.
    Alexander R Oles, Peter Y Yu, Abasi-Ama Udeme, Sudarshana Sharma, Priya Londhe, Benjamin R Pryce, Erin E Talbert, Eric M Hill, Carlos J Miranda, Brian K Kaspar, Michael A Arnold, Jack Hyland, Cheryl A London, Peter J Houghton, David J Wang, Ryan D Roberts, Denis C Guttridge.
      Rhabdomyosarcoma (RMS) is the most common soft tissue cancer among children, characterized by a skeletal muscle lineage that is impaired from undergoing terminal differentiation. NF-κB is constitutively active in cancer cells and plays a critical role in cell survival. Although NF-κB is also activated in RMS, surprisingly, we find that these tumors are far less dependent on NF-κB for their survival. Instead, RMS cells survive, paradoxically, by being partially differentiated under the control of the myogenic transcription factor MyoD. Loss of MyoD, or cellular reprogramming, dedifferentiates RMS tumor cells and sensitizes their death under stress. MyoD enhances RMS survival by regulating DNA methyltransferases, which in turn suppresses the tumor suppressor and pro-apoptotic gene CYLD. From these findings, we propose that MyoD acts as an oncogene in RMS by enhancing survival through pro-differentiation and anti-cell death activities.
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113149
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