bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–03–23
nineteen papers selected by
Connor Rogerson, University of Cambridge
  1. Inference of transcriptional regulation from STARR-seq data.
  2. Genome-wide CRISPR screen identifies IRF1 and TFAP4 as transcriptional regulators of Galectin-9 in T cell acute lymphoblastic leukemia.
  3. Identifying cross-lineage dependencies of cell-type-specific regulators in mouse gastruloids.
  4. Overlapping and distinct functions of SPT6, PNUTS, and PCF11 in regulating transcription termination.
  5. Binding domain mutations provide insight into CTCF's relationship with chromatin and its contribution to gene regulation.
  6. Human MeCP2 binds to promoters and inhibits transcription in an unmethylated yeast genome.
  7. Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus.
  8. The Sotos syndrome gene Nsd1 safeguards developmental gene enhancers poised for transcription by maintaining the precise deposition of histone methylation.
  9. Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming.
  10. MyoD1 localization at the nuclear periphery is mediated by association of WFS1 with active enhancers.
  11. Matrix stiffness modulates androgen response genes and chromatin state in prostate cancer.
  12. Recurrent breakpoints in the BRD4 locus reduce toxicity associated with gene amplification.
  13. SIP2 is the master transcription factor of Plasmodium merozoite formation.
  14. A bHLH interaction code controls bipotential differentiation and self-renewal in the Drosophila gut.
  15. CacPred: a cascaded convolutional neural network for TF-DNA binding prediction.
  16. Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer.
  17. MOSim: bulk and single-cell multilayer regulatory network simulator.
  18. Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin.
  19. Dynamic regulation of murine RNA Polymerase III transcription during heat shock stress.
  1. Phys Rev E. 2025 Feb;111(2-1): 024402
    Inference of transcriptional regulation from STARR-seq data.
    Amin Safaeesirat, Hoda Taeb, Emirhan Tekoglu, Tunc Morova, Nathan A Lack, Eldon Emberly.
      One of the primary regulatory processes in cells is transcription, during which RNA polymerase II (Pol-II) transcribes DNA into RNA. The binding of Pol-II to its site is regulated through interactions with transcription factors (TFs) that bind to DNA at enhancer cis-regulatory elements. Measuring the enhancer activity of large libraries of distinct DNA sequences is now possible using massively parallel reporter assays (MPRAs), and computational methods have been developed to identify the dominant statistical patterns of TF binding within these large datasets. Such methods are global in their approach and may overlook important regulatory sites that function only within the local context. Here we introduce a method for inferring functional regulatory sites (their number, location, and width) within an enhancer sequence based on measurements of its transcriptional activity from an MPRA method such as STARR-seq. The model is based on a mean-field thermodynamic description of Pol-II binding that includes interactions with bound TFs. Our method applied to simulated STARR-seq data for a variety of enhancer architectures shows how data quality impacts the inference and also how it can find local regulatory sites that may be missed in a global approach. We also apply the method to recently measured STARR-seq data on androgen receptor (AR) bound sequences, a TF that plays an important role in the regulation of prostate cancer. The method identifies key regulatory sites within these sequences, which are found to overlap with binding sites of known coregulators of AR.
    DOI:  https://doi.org/10.1103/PhysRevE.111.024402
  2. Sci Adv. 2025 Mar 21. 11(12): eads8351
    Genome-wide CRISPR screen identifies IRF1 and TFAP4 as transcriptional regulators of Galectin-9 in T cell acute lymphoblastic leukemia.
    Caroline R M Wiggers, Burak Yüzügüldü, Nathanial G Tadros, Tayla B Heavican-Foral, Eugene Y Cho, Zachary C Eisenbies, Merve Ozdemir, Steffen B Kulp, Yun-Cheol Chae, Alejandro Gutierrez, Jens G Lohr, Birgit Knoechel.
      Galectin-9 is overexpressed in a variety of cancers and associated with worse clinical outcome in some cancers. However, the regulators driving Galectin-9 expression are unknown. Here, we defined the transcriptional regulators and epigenetic circuitry of Galectin-9 in pediatric T cell acute lymphoblastic leukemia (T-ALL), as an example of a disease with strong Galectin-9 expression, in which higher expression was associated with lower overall survival. By performing a genome-wide CRISPR screen, we identified the transcription factors IRF1 and TFAP4 as key regulators for Galectin-9 expression by binding its regulatory elements. Whereas IRF1 was observed exclusively on the promoter, TFAP4 binding was detected at an enhancer solely in T-ALL cells associated with higher Galectin-9 levels. Together, our results show that IRF1 is responsible and indispensable for Galectin-9 expression and TFAP4 further fine-tunes its expression. Our approach, a flow-based genome-wide CRISPR screen complemented by transcription factor binding and enhancer mapping, creates innovative opportunities for understanding and manipulating epigenetic transcriptional regulation in cancer.
    DOI:  https://doi.org/10.1126/sciadv.ads8351
  3. Dev Cell. 2025 Mar 11. pii: S1534-5807(25)00118-2. [Epub ahead of print]
    Identifying cross-lineage dependencies of cell-type-specific regulators in mouse gastruloids.
    Luca Braccioli, Teun van den Brand, Noemi Alonso Saiz, Charis Fountas, Patrick H N Celie, Justina Kazokaitė-Adomaitienė, Elzo de Wit.
      Correct gene expression levels are crucial for normal development. Advances in genomics enable the inference of gene regulatory programs active during development but cannot capture the complex multicellular interactions occurring during mammalian embryogenesis in utero. In vitro models of mammalian development, like gastruloids, can overcome this limitation. Using time-resolved single-cell chromatin accessibility analysis, we delineated the regulatory profile during mouse gastruloid development, identifying critical drivers of developmental transitions. Gastruloids develop from bipotent progenitor cells driven by the transcription factors (TFs) OCT4, SOX2, and TBXT, differentiating into the mesoderm (characterized by the mesogenin 1 [MSGN1]) and spinal cord (characterized by CDX2). ΔCDX gastruloids fail to form spinal cord, while Msgn1 ablation inhibits paraxial mesoderm and spinal cord development. Chimeric gastruloids with ΔMSGN1 and wild-type cells formed both tissues, indicating that inter-tissue communication is necessary for spinal cord formation. Our work has important implications for studying inter-tissue communication and gene regulatory programs in development.
    Keywords:  chromatin accessibility; gastruloid; inter-tissue communication; mesoderm; single-cell ATAC-seq; spinal cord; transcription factor
    DOI:  https://doi.org/10.1016/j.devcel.2025.02.013
  4. Nucleic Acids Res. 2025 Feb 27. pii: gkaf179. [Epub ahead of print]53(5):
    Overlapping and distinct functions of SPT6, PNUTS, and PCF11 in regulating transcription termination.
    Fabienne Bejjani, Emmanuel Ségéral, Kevin Mosca, Adriana Lecourieux, May Bakail, Meriem Hamoudi, Stéphane Emiliani.
      The histone chaperone and transcription elongation factor SPT6 is integral to RNA polymerase II (RNAPII) activity. SPT6 also plays a crucial role in regulating transcription termination, although the mechanisms involved are largely unknown. In an attempt to identify the pathways employed by SPT6 in this regulation, we found that, while SPT6 and its partner IWS1 interact and co-localize with RNAPII, their functions diverge significantly at gene termination sites. Depletion of SPT6, but not of IWS1, results in extensive readthrough transcription, indicating that SPT6 independently regulates transcription termination. Further analysis identified that the cleavage and polyadenylation factor PCF11 and the phosphatase regulatory protein PNUTS collaborate with SPT6 in this process. These findings suggest that SPT6 may facilitate transcription termination by recruiting PNUTS and PCF11 to RNAPII. Additionally, SPT6 and PNUTS jointly restrict promoter upstream transcripts (PROMPTs), whereas PCF11 presence is essential for their accumulation in the absence of SPT6 at hundreds of genes. Thus, SPT6, PCF11, and PNUTS have both distinct and overlapping functions in transcription termination. Our data highlight the pivotal role of SPT6 in ensuring proper transcription termination at the 5' and 3'-ends of genes.
    DOI:  https://doi.org/10.1093/nar/gkaf179
  5. Cell Genom. 2025 Mar 18. pii: S2666-979X(25)00069-2. [Epub ahead of print] 100813
    Binding domain mutations provide insight into CTCF's relationship with chromatin and its contribution to gene regulation.
    Catherine Do, Guimei Jiang, Giulia Cova, Christos C Katsifis, Domenic N Narducci, Theodore Sakellaropoulos, Raphael Vidal, Priscillia Lhoumaud, Aristotelis Tsirigos, Faye Fara D Regis, Nata Kakabadze, Elphege P Nora, Marcus Noyes, Anders S Hansen, Jane A Skok.
      Here we used a series of CTCF mutations to explore CTCF's relationship with chromatin and its contribution to gene regulation. CTCF's impact depends on the genomic context of bound sites and the unique binding properties of WT and mutant CTCF proteins. Specifically, CTCF's signal strength is linked to changes in accessibility, and the ability to block cohesin is linked to its binding stability. Multivariate modeling reveals that both CTCF and accessibility contribute independently to cohesin binding and insulation, but CTCF signal strength has a stronger effect. CTCF and chromatin have a bidirectional relationship such that at CTCF sites, accessibility is reduced in a cohesin-dependent, mutant-specific fashion. In addition, each mutant alters TF binding and accessibility in an indirect manner, changes which impart the most influence on rewiring transcriptional networks and the cell's ability to differentiate. Collectively, the mutant perturbations provide a rich resource for determining CTCF's site-specific effects.
    Keywords:  CTCF; CTCF mutations; cancer; chromatin accessibility; chromatin organization; cohesin; gene regulation; neurological disorder; residence time
    DOI:  https://doi.org/10.1016/j.xgen.2025.100813
  6. Genetics. 2025 Mar 18. pii: iyaf043. [Epub ahead of print]
    Human MeCP2 binds to promoters and inhibits transcription in an unmethylated yeast genome.
    Joshua A R Brown, Maggie Y M Ling, Juan Ausió, LeAnn J Howe.
      MeCP2 is a DNA-binding transcriptional regulator that is present at near-histone levels in mammalian cortical neurons. Originally identified as a DNA methylation reader, MeCP2 has been proposed to repress transcription by recruiting corepressors to methylated DNA. While some genome-wide occupancy studies support a preference for methylated DNA, others suggest that MeCP2 binding is more influenced by DNA sequence and accessibility than methylation status. Moreover, multiple studies also suggest a role for MeCP2 in gene activation. To clarify its function, we expressed MeCP2 in Saccharomyces cerevisiae, which lacks DNA methylation and known MeCP2 corepressors. We find that MeCP2 is toxic to yeast and globally inhibits transcription, indicating that MeCP2 can have significant functional impacts without DNA methylation or mammalian corepressors. A subset of MeCP2 mutations that cause the neurodevelopmental disorder Rett syndrome, particularly those that map to the DNA binding domain, alleviate the toxicity of MeCP2 in yeast. Consistent with the importance of DNA binding for growth inhibition, we show that MeCP2 binds to the yeast genome, with increased occupancy at GC-rich, nucleosome-depleted sequences. These findings present yeast as a useful tool for analyzing MeCP2 and reveal MeCP2 properties that are not strictly dependent on DNA methylation or mammalian corepressors.
    Keywords:   S. cerevisiae ; MeCP2; Rett syndrome; transcription repression
    DOI:  https://doi.org/10.1093/genetics/iyaf043
  7. Elife. 2025 Mar 21. pii: RP102019. [Epub ahead of print]14
    Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus.
    Akanksha Bafna, Gareth Banks, Vadim Vasilyev, Robert Dallmann, Michael H Hastings, Patrick M Nolan.
      The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn coordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing to map the genomic localization of ZFHX3-binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites, co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12 h light-12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.
    Keywords:  SCN; circadian rhythm; genetics; genomics; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.102019
  8. J Biol Chem. 2025 Mar 19. pii: S0021-9258(25)00272-8. [Epub ahead of print] 108423
    The Sotos syndrome gene Nsd1 safeguards developmental gene enhancers poised for transcription by maintaining the precise deposition of histone methylation.
    Jie Li, Zhucui Li, Jiekai Yin, Yinsheng Wang, Deyou Zheng, Ling Cai, Gang Greg Wang.
      Germline haploinsufficiency of NSD1 is implicated as the etiology of Sotos syndrome; however, the underlying mechanism remains far from being clear. Here, we use mouse embryonic stem cell (mESC) differentiation as a model system to address this question. We found Nsd1 to be indispensable for the faithful differentiation of mESCs into three primary germ layers, particularly, various meso-endodermal cell lineages related to development of the heart and the skeletal system. Time-course transcriptomic profiling following the mESC differentiation revealed that Nsd1 not only facilitates the basal expression but also permits the differentiation-accompanied rapid induction of a suite of meso-endoderm lineage-specifying transcription factor (TF) genes such as T and Gata4. Mechanistically, Nsd1 directly occupies putative distal enhancers of the lineage TF genes under the pluripotent cell state, where it deposits H3K36me2 to antagonizes the excessive H3K27me3 and maintain the basal H3K27ac level, thereby safeguarding these gene enhancers at a primed state that responds readily to differentiation cues. In agreement, gene rescue assays using the Nsd1 knockout mESCs showed that the H3K36me2 catalysis by Nsd1 requires several functional modules within Nsd1 (namely, PHD1-4, PWWP2 and SET) to a similar degree. Disruption of either one of these Nsd1 modules severely abrogated H3K36me2 in mESCs and significantly impaired appropriate induction of developmental genes upon mESC differentiation. Altogether, our study provides novel molecular insight into how the NSD1 perturbation derails normal development and causes the disease.
    Keywords:  H3K27ac; H3K27me3; H3K36me2; Nsd1; Sotos syndrome; development; differentiation; gene enhancer
    DOI:  https://doi.org/10.1016/j.jbc.2025.108423
  9. Cell Stem Cell. 2025 Mar 19. pii: S1934-5909(25)00083-9. [Epub ahead of print]
    Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming.
    Gerrald A Lodewijk, Sayaka Kozuki, Clara J Han, Benjamin R Topacio, Seungho Lee, Lily Nixon, Abolfazl Zargari, Gavin Knight, Randolph Ashton, Lei S Qi, S Ali Shariati.
      Embryonic stem cells (ESCs) can self-organize into structures with spatial and molecular similarities to natural embryos. During development, embryonic and extraembryonic cells differentiate through activation of endogenous regulatory elements while co-developing via cell-cell interactions. However, engineering regulatory elements to self-organize ESCs into embryo models remains underexplored. Here, we demonstrate that CRISPR activation (CRISPRa) of two regulatory elements near Gata6 and Cdx2 generates embryonic patterns resembling pre-gastrulation mouse embryos. Live single-cell imaging revealed that self-patterning occurs through orchestrated collective movement driven by cell-intrinsic fate induction. In 3D, CRISPRa-programmed embryo models (CPEMs) exhibit morphological and transcriptomic similarity to pre-gastrulation mouse embryos. CPEMs allow versatile perturbations, including dual Cdx2-Elf5 activation to enhance trophoblast differentiation and lineage-specific activation of laminin and matrix metalloproteinases, uncovering their roles in basement membrane remodeling and embryo model morphology. Our findings demonstrate that minimal intrinsic epigenome editing can self-organize ESCs into programmable pre-gastrulation embryo models with robust lineage-specific perturbation capabilities.
    Keywords:  CRISPRa; Collective Motion; embryo models; embryonic patterning; epigenome editing; synthetic biology
    DOI:  https://doi.org/10.1016/j.stem.2025.02.015
  10. Nat Commun. 2025 Mar 17. 16(1): 2614
    MyoD1 localization at the nuclear periphery is mediated by association of WFS1 with active enhancers.
    Konstantina Georgiou, Fatih Sarigol, Tobias Nimpf, Christian Knapp, Daria Filipczak, Roland Foisner, Nana Naetar.
      Spatial organization of the mammalian genome influences gene expression and cell identity. While association of genes with the nuclear periphery is commonly linked to transcriptional repression, also active, expressed genes can localize at the nuclear periphery. The transcriptionally active MyoD1 gene, a master regulator of myogenesis, exhibits peripheral localization in proliferating myoblasts, yet the underlying mechanisms remain elusive. Here, we generate a reporter cell line to demonstrate that peripheral association of the MyoD1 locus is independent of mechanisms involved in heterochromatin anchoring. Instead, we identify the nuclear envelope transmembrane protein WFS1 that tethers MyoD1 to the nuclear periphery. WFS1 primarily associates with active distal enhancer elements upstream of MyoD1, and with a subset of enhancers genome-wide, which are enriched in active histone marks and linked to expressed myogenic genes. Overall, our data identify a mechanism involved in tethering regulatory elements of active genes to the nuclear periphery.
    DOI:  https://doi.org/10.1038/s41467-025-57758-x
  11. NAR Cancer. 2025 Mar;7(1): zcaf010
    Matrix stiffness modulates androgen response genes and chromatin state in prostate cancer.
    Roosa Kaarijärvi, Heidi Kaljunen, Onni Niemi, Merja Räsänen, Ville Paakinaho, Kirsi Ketola.
      The interplay between the extracellular matrix (ECM) and prostate cancer has been shown to increase ECM stiffness, correlating with more aggressive disease forms. However, the impact of ECM stiffness on the androgen receptor (AR), a key target in prostate cancer treatment, remains elusive. Here, we investigated whether matrix stiffness influences prostate cancer progression, transcriptional regulation, chromatin state, and AR function in AR-positive prostate cancer cells under varying ECM stiffness conditions. We utilized ATAC-seq (assay for transposase-accessible chromatin with sequencing) and RNA sequencing under different ECM conditions, along with the SUC2 metastatic prostate adenocarcinoma patient dataset, to investigate the role of ECM stiffness in chromatin state and androgen response genes, as well as its impact on prostate cancer progression. Results demonstrated that increased ECM stiffness elevated the expression of genes related to proliferation and differentiation. In contrast, androgen response genes were most highly induced in soft ECM conditions. Integrating chromatin accessibility with transcriptomic data revealed that androgen response genes were more transcriptionally available in soft ECM conditions. Additionally, increased ECM stiffness upregulated genes associated with low overall survival in the SUC2 dataset. Taken together, our results indicate that high expression of hard matrix stiffness genes may promote prostate cancer progression, leading to more aggressive disease forms associated with poor survival.
    DOI:  https://doi.org/10.1093/narcan/zcaf010
  12. Cell Genom. 2025 Mar 14. pii: S2666-979X(25)00071-0. [Epub ahead of print] 100815
    Recurrent breakpoints in the BRD4 locus reduce toxicity associated with gene amplification.
    Jeremiah Wala, Simona Dalin, Sophie Webster, Ofer Shapira, John Busanovich, Shahab Sarmashghi, Rameen Beroukhim, Pratiti Bandopadhayay, Veronica Rendo.
      Recent work by the ICGC-PCAWG consortium identified recurrent focal deletions in the BRD4 gene, decreasing expression despite increased copy number. We show that these focal deletions occur in the context of cyclin E1 amplification in breast, ovarian, and endometrial cancers, and serve to disrupt BRD4 regulatory regions and gene expression across isoforms. We analyze open reading frame screen data and find that overexpression of BRD4 long (BRD4-L) and short isoform BRD4-S(a) impairs cell growth across cell lines. We confirm these results in OVSAHO ovarian cancer cells, where the overexpression of BRD4 isoforms significantly reduces tumor growth. Next, we mimic BRD4 focal deletions using CRISPR-Cas9 technology and show that these focal deletions rescue ovarian cancer cells from toxicity associated with BRD4 overexpression, suggesting that BRD4 levels must be fine-tuned for cancer cell proliferation. Our study provides experimental evidence for the first recurrent deletion reducing toxicity in cancer, expanding the landscape of cancer progression mechanisms.
    Keywords:  BRD4; CRISPR-Cas9; PCAWG consortium; breast cancer; gene amplification; gene isoforms; ovarian cancer; structural variants; toxic gene
    DOI:  https://doi.org/10.1016/j.xgen.2025.100815
  13. Sci Adv. 2025 Mar 21. 11(12): eads5458
    SIP2 is the master transcription factor of Plasmodium merozoite formation.
    Tsubasa Nishi, Izumi Kaneko, Masao Yuda.
      Malaria, one of the most serious infectious diseases worldwide, is caused by the proliferation of Plasmodium parasites through repeated cycles of intraerythrocytic development. The parasite replicates via schizogony in host erythrocytes, producing multiple progeny merozoites that invade new erythrocytes. Although merozoite formation is the most crucial step in malaria pathogenesis, its molecular mechanism remains unclear. SIP2 is an AP2 transcription factor expressed during schizogony and is particularly conserved among erythrocyte-infecting apicomplexan parasites. Here, we reveal that SIP2 in Plasmodium berghei (PbSIP2) functions as the master transcription factor for merozoite formation. Conditional disruption of pbsip2 resulted in developmental arrest before merozoite formation and notable down-regulation of merozoite-related genes. ChIP-seq showed that PbSIP2 comprehensively activated merozoite-related genes by binding to previously reported cis-regulatory elements of merozoite invasion-related genes, including the bipartite motif (TGCAN4-6GTGCA). Collectively, our results indicate that SIP2 is a transcription factor that establishes erythrocyte infectivity and may have an evolutionary origin from the common ancestor of erythrocyte-infecting apicomplexan parasites.
    DOI:  https://doi.org/10.1126/sciadv.ads5458
  14. Cell Rep. 2025 Mar 14. pii: S2211-1247(25)00169-X. [Epub ahead of print]44(3): 115398
    A bHLH interaction code controls bipotential differentiation and self-renewal in the Drosophila gut.
    Aleix Puig-Barbe, Svenja Dettmann, Vinícius Dias Nirello, Helen Moor, Sina Azami, Bruce A Edgar, Patrick Varga-Weisz, Jerome Korzelius, Joaquín de Navascués.
      Multipotent adult stem cells balance self-renewal with differentiation into various cell types. How this balance is regulated at the transcriptional level is poorly understood. Here, we show that a network of basic helix-loop-helix (bHLH) transcription factors controls both stemness and bipotential differentiation in the Drosophila adult intestine. We find that homodimers of Daughterless (Da), a homolog of mammalian E proteins, maintain self-renewal of intestinal stem cells (ISCs), antagonizing the enteroendocrine fate promoted by heterodimers of Da and Scute (Sc; homolog of ASCL). The HLH factor Extramacrochaetae (Emc; homologous to Id proteins) promotes absorptive differentiation by titrating Da and Sc. Emc prevents the committed absorptive progenitor from dedifferentiating, underscoring the plasticity of these cells. Switching physical interaction partners in this way enables the active maintenance of stemness while priming stem cells for differentiation along two alternative fates. Such regulatory logic is likely operative in other bipotent stem cell systems.
    Keywords:  CP: Stem cell research; Notch signaling; bHLH; bipotent stem cell; differentiation; intestinal stem cell; stemness
    DOI:  https://doi.org/10.1016/j.celrep.2025.115398
  15. BMC Genomics. 2025 Mar 18. 26(Suppl 2): 264
    CacPred: a cascaded convolutional neural network for TF-DNA binding prediction.
    Shuangquan Zhang, Anjun Ma, Xuping Xie, Zhichao Lian, Yan Wang.
       BACKGROUND: Transcription factors (TFs) regulate the genes' expression by binding to DNA sequences. Aligned TFBSs of the same TF are seen as cis-regulatory motifs, and substantial computational efforts have been invested to find motifs. In recent years, convolutional neural networks (CNNs) have succeeded in TF-DNA binding prediction, but existing DL methods' accuracy needs to be improved and convolution function in TF-DNA binding prediction should be further explored.
    RESULTS: We develop a cascaded convolutional neural network model named CacPred to predict TF-DNA binding on 790 Chromatin immunoprecipitation-sequencing (ChIP-seq) datasets and seven ChIP-nexus (chromatin immunoprecipitation experiments with nucleotide resolution through exonuclease, unique barcode, and single ligation) datasets. We compare CacPred to six existing DL models across nine standard evaluation metrics. Our results indicate that CacPred outperforms all comparison models for TF-DNA binding prediction, and the average accuracy (ACC), matthews correlation coefficient (MCC), and the area of eight metrics radar (AEMR) are improved by 3.3%, 9.2%, and 6.4% on 790 ChIP-seq datasets. Meanwhile, CacPred improves the average ACC, MCC, and AEMR of 5.5%, 16.8%, and 12.9% on seven ChIP-nexus datasets. To explain the proposed method, motifs are used to show features CacPred learned. In light of the results, CacPred can find some significant motifs from input sequences.
    CONCLUSIONS: This paper indicates that CacPred performs better than existing models on ChIP-seq data. Seven ChIP-nexus datasets are also analyzed, and they coincide with results that our proposed method performs the best on ChIP-seq data. CacPred only is equipped with the convolutional algorithm, demonstrating that pooling processing of the existing models leads to losing some sequence information. Some significant motifs are found, showing that CacPred can learn features from input sequences. In this study, we demonstrate that CacPred is an effective and feasible model for predicting TF-DNA binding. CacPred is freely available at https://github.com/zhangsq06/CacPred .
    Keywords:  ChIP-seq; Deep learning; TF-DNA binding prediction; Transcription factor
    DOI:  https://doi.org/10.1186/s12864-025-11399-y
  16. Nat Cancer. 2025 Mar 18.
    Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer.
    Hanling Wang, Sulin Zhang, Qiang Pan, Jiacheng Guo, Ni Li, Lifan Chen, Junyu Xu, Jingyi Zhou, Yongqiang Gu, Xuege Wang, Guoying Zhang, Yannan Lian, Wei Zhang, Naiheng Lin, Zige Jin, Yi Zang, Weihua Lan, Xiaoyan Cheng, Minjia Tan, Fei Xavier Chen, Jun Jiang, Qiuli Liu, Mingyue Zheng, Jun Qin.
      The transdifferentiation from adenocarcinoma to neuroendocrine prostate cancer (NEPC) in men confers antiandrogen therapy resistance. Here our analysis combining CRISPR‒Cas9 screening with single-cell RNA sequencing tracking of tumor transition demonstrated that antiandrogen-induced zinc finger MYND-type containing 8 (ZMYND8)-dependent epigenetic programming orchestrates NEPC transdifferentiation. Ablation of Zmynd8 prevents NEPC development, while ZMYND8 upregulation mediated by achaete-scute homolog 1 promotes NEPC differentiation. We show that forkhead box protein M1 (FOXM1) stabilizes ZMYND8 binding to chromatin regions characterized by H3K4me1-H3K14ac modification and FOXM1 targeting. Antiandrogen therapy releases the SWI/SNF chromatin remodeling complex from the androgen receptor, facilitating its interaction with ZMYND8-FOXM1 to upregulate critical neuroendocrine lineage regulators. We develop iZMYND8-34, a small molecule designed to inhibit ZMYND8's histone recognition, which effectively blocks NEPC development. These findings reveal the critical role of ZMYND8-dependent epigenetic programming induced by androgen deprivation therapy in orchestrating lineage fate. Targeting ZMYND8 emerges as a promising strategy for impeding NEPC development.
    DOI:  https://doi.org/10.1038/s43018-025-00928-z
  17. Brief Bioinform. 2025 Mar 04. pii: bbaf110. [Epub ahead of print]26(2):
    MOSim: bulk and single-cell multilayer regulatory network simulator.
    Carolina Monzó, Maider Aguerralde-Martin, Carlos Martínez-Mira, Ángeles Arzalluz-Luque, Ana Conesa, Sonia Tarazona.
      As multi-omics sequencing technologies advance, the need for simulation tools capable of generating realistic and diverse (bulk and single-cell) multi-omics datasets for method testing and benchmarking becomes increasingly important. We present MOSim, an R package that simulates both bulk (via mosim function) and single-cell (via sc_mosim function) multi-omics data. The mosim function generates bulk transcriptomics data (RNA-seq) and additional regulatory omics layers (ATAC-seq, miRNA-seq, ChIP-seq, Methyl-seq, and transcription factors), while sc_mosim simulates single-cell transcriptomics data (scRNA-seq) with scATAC-seq and transcription factors as regulatory layers. The tool supports various experimental designs, including simulation of gene co-expression patterns, biological replicates, and differential expression between conditions. MOSim enables users to generate quantification matrices for each simulated omics data type, capturing the heterogeneity and complexity of bulk and single-cell multi-omics datasets. Furthermore, MOSim provides differentially abundant features within each omics layer and elucidates the active regulatory relationships between regulatory omics and gene expression data at both bulk and single-cell levels. By leveraging MOSim, researchers will be able to generate realistic and customizable bulk and single-cell multi-omics datasets to benchmark and validate analytical methods specifically designed for the integrative analysis of diverse regulatory omics data.
    Keywords:  bulk; multi-omic simulator; single cell; transcriptomics
    DOI:  https://doi.org/10.1093/bib/bbaf110
  18. Mol Cell. 2025 Mar 11. pii: S1097-2765(25)00147-9. [Epub ahead of print]
    Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin.
    Xiang Huang, Jie Zhang, Yixian Cun, Meijun Ye, Zhijun Ren, Wenbing Guo, Xiaojun Ma, Jiayin Liu, Weiwei Luo, Xiang Sun, Jingwen Shao, Zehong Wu, Xiaofeng Zhu, Jinkai Wang.
      Interaction between the N6-methyladenosine (m6A) methyltransferase METTL3 and METTL14 is critical for METTL3 to deposit m6A on various types of RNAs. It remains to be uncovered whether there is spatial control of m6A deposition on different types of RNAs. Here, through genome-wide CRISPR-Cas9 screening in the A549 cell line, we find that H3K27ac acetylase p300-mediated METTL3 acetylation suppresses the binding of METTL3 on H3K27ac-marked chromatin by inhibiting its interaction with METTL14. Consistently, p300 catalyzing the acetylation of METTL3 specifically occurs on H3K27ac-marked chromatin. Disruptive mutations on METTL3 acetylation sites selectively promote the m6A of chromatin-associated RNAs from p300-bound enhancers and promoters marked by H3K27ac, resulting in transcription inhibition of ferroptosis-inhibition-related genes. In addition, PAK2 promotes METTL3 acetylation by phosphorylating METTL3. Inhibition of PAK2 promotes ferroptosis in a manner that depends on the acetylation of METTL3. Our study reveals a spatial-selective way to specifically regulate the deposition of m6A on enhancer and promoter RNAs.
    Keywords:  H3K27ac; METTL3; PAK2; chromatin-associated RNA; m(6)A; p300
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.016
  19. Genetics. 2025 Mar 18. pii: iyaf042. [Epub ahead of print]
    Dynamic regulation of murine RNA Polymerase III transcription during heat shock stress.
    Thomas F Nguyen, James Z J Kwan, Jennifer E Mitchell, Jieying H Cui, Sheila S Teves.
      Cells respond to many different types of stresses by overhauling gene expression patterns, both at the transcriptional and translational level. Under heat stress, global transcription and translation are inhibited, while the expression of chaperone proteins are preferentially favored. As the direct link between mRNA transcription and protein translation, tRNA expression is intricately regulated during the stress response. Despite extensive research into the heat shock response (HSR), the regulation of tRNA expression by RNA Polymerase III (Pol III) transcription has yet to be fully elucidated in mammalian cells. Here, we examine the regulation of Pol III transcription during different stages of heat shock stress in mouse embryonic stem cells (mESCs). We observe that Pol III transcription is downregulated after 30 minutes of heat shock, followed by an overall increase in transcription after 60 minutes of heat shock. This effect is more evident in tRNAs, though other Pol III gene targets are also similarly affected. Notably, we show that the downregulation at 30 minutes of heat shock is independent of HSF1, the master transcription factor of the HSR, but that the subsequent increase in expression at 60 minutes requires HSF1. Taken together, these results demonstrate an adaptive RNA Pol III response to heat stress, and an intricate relationship between the canonical HSR and tRNA expression.
    Keywords:  heat shock; mouse embryonic stem cells; transcription; transfer RNA
    DOI:  https://doi.org/10.1093/genetics/iyaf042
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