bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–04–27
eighteen papers selected by
Connor Rogerson, University of Cambridge
  1. The SWI/SNF PBAF complex facilitates REST occupancy at repressive chromatin.
  2. Polymer model integrates imaging and sequencing to reveal how nanoscale heterochromatin domains influence gene expression.
  3. α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells.
  4. MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.
  5. Identifying reproducible transcription regulator coexpression patterns with single cell transcriptomics.
  6. The mechanism of YAP/TAZ transactivation and dual targeting for cancer therapy.
  7. RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.
  8. Integrated analysis of molecular atlases unveils modules driving developmental cell subtype specification in the human cortex.
  9. BRD9 functions as a methylarginine reader to regulate AKT-EZH2 signaling.
  10. Transcriptome-wide analysis of differential expression in perturbation atlases.
  11. Human de novo mutation rates from a four-generation pedigree reference.
  12. MYCN and KAT2A form a feedforward loop to drive an oncogenic transcriptional program in neuroblastoma.
  13. In Vitro Assembly of Nucleosomes for Binding/Remodeling Assays.
  14. Joint analysis of chromatin accessibility and gene expression in the same single cells reveals cancer-specific regulatory programs.
  15. The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.
  16. IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies.
  17. Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and function.
  18. Preparation for mitosis requires gradual CDK1 activation.
  1. Mol Cell. 2025 Apr 16. pii: S1097-2765(25)00303-X. [Epub ahead of print]
    The SWI/SNF PBAF complex facilitates REST occupancy at repressive chromatin.
    Elena Grossi, Christie B Nguyen, Saul Carcamo, Valentina Kirigin Callaú, Shannon Moran, Dan Filipescu, Somnath Tagore, Tessa M Firestone, Michael-Christopher Keogh, Lu Sun, Benjamin Izar, Dan Hasson, Emily Bernstein.
      SWI/SNF (switch/sucrose non-fermentable) chromatin remodelers possess unique functionalities difficult to dissect. Distinct cancers harbor mutations in specific subunits, such as the polybromo-associated BAF (PBAF)-specific component ARID2 in melanoma. Here, we perform epigenomic profiling of SWI/SNF complexes and their associated chromatin states in melanocytes and melanoma. Time-resolved approaches reveal that PBAF regions are generally less sensitive to ATPase inhibition than BAF sites. We further uncover a subset of PBAF-exclusive regions within Polycomb-repressed chromatin that are enriched for REST (RE1 silencing transcription factor), a transcription factor that represses neuronal genes. In turn, PBAF complex disruption via ARID2 loss hinders REST's ability to bind and inactivate its targets, leading to upregulation of synaptic transcripts. Remarkably, this gene signature is conserved in melanoma patients with ARID2 mutations and correlates with an expression program enriched in melanoma brain metastases. Overall, we demonstrate a unique role for PBAF in generating accessibility for a silencing transcription factor at repressed chromatin, with important implications for disease.
    Keywords:  ARID2; PBAF; Polycomb; REST; SWI/SNF; chromatin remodelers; melanoma; transcription factors
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.026
  2. Nat Commun. 2025 Apr 23. 16(1): 3816
    Polymer model integrates imaging and sequencing to reveal how nanoscale heterochromatin domains influence gene expression.
    Vinayak Vinayak, Ramin Basir, Rosela Golloshi, Joshua Toth, Lucas Sant'Anna, Melike Lakadamyali, Rachel Patton McCord, Vivek B Shenoy.
      Chromatin organization regulates gene expression, with nanoscale heterochromatin domains playing a fundamental role. Their size varies with microenvironmental stiffness and epigenetic interventions, but how these factors regulate their formation and influence transcription remains unclear. To address this, we developed a sequencing-informed copolymer model that simulates chromatin evolution through diffusion and active epigenetic reactions. Our model predicts the formation of nanoscale heterochromatin domains and quantifies how domain size scales with epigenetic reaction rates, showing that epigenetic and compaction changes primarily occur at domain boundaries. We validated these predictions via Hi-C and super-resolution imaging of hyperacetylated melanoma cells and identified differential expression of metastasis-related genes through RNA-seq. We validated our findings in hMSCs, where epigenetic reaction rates respond to microenvironmental stiffness. Conclusively, our simulations reveal that heterochromatin domain boundaries regulate gene expression and epigenetic memory. These findings demonstrate how external cues drive chromatin organization and transcriptional memory in development and disease.
    DOI:  https://doi.org/10.1038/s41467-025-59001-z
  3. Nat Cell Biol. 2025 Apr 23.
    α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells.
    Karlien Van Nerum, Anne Wenzel, Lidia Argemi-Muntadas, Eleni Kafkia, Antar Drews, Ida Sophie Brun, Viktoria Lavro, Annina Roelofsen, Nikolaos Stamidis, Sandra Bages Arnal, Cheng Zhao, Simone di Sanzo, Moritz Völker-Albert, Sophie Petropoulos, Thomas Moritz, Jan Jakub Żylicz.
      Development and lineage choice are driven by interconnected transcriptional, epigenetic and metabolic changes. Specific metabolites, such as α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin-modifying enzymes. However, how metabolism coordinates cell-state changes, especially in human pre-implantation development, remains unclear. Here we uncover that inducing naive human embryonic stem cells towards the trophectoderm lineage results in considerable metabolic rewiring, characterized by αKG accumulation. Elevated αKG levels potentiate the capacity of naive embryonic stem cells to specify towards the trophectoderm lineage. Moreover, increased αKG levels promote blastoid polarization and trophectoderm maturation. αKG supplementation does not affect global histone methylation levels; rather, it decreases acetyl-CoA availability, reduces histone acetyltransferase activity and weakens the pluripotency network. We propose that metabolism functions as a positive feedback loop aiding in trophectoderm fate induction and maturation, highlighting that global metabolic rewiring can promote specificity in cell fate decisions through intricate regulation of signalling and chromatin.
    DOI:  https://doi.org/10.1038/s41556-025-01658-1
  4. Sci Adv. 2025 Apr 25. 11(17): eadt3177
    MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.
    Brian Freie, Ali H Ibrahim, Patrick A Carroll, Roderick T Bronson, Arnaud Augert, David MacPherson, Robert N Eisenman.
      The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma, and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting Max across multiple mouse neuroendocrine tissues, we find that Max inactivation alone produces pituitary adenomas, while Max inactivation cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a marked shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival, and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.
    DOI:  https://doi.org/10.1126/sciadv.adt3177
  5. PLoS Comput Biol. 2025 Apr;21(4): e1012962
    Identifying reproducible transcription regulator coexpression patterns with single cell transcriptomics.
    Alexander Morin, Ching Pan Chu, Paul Pavlidis.
      The proliferation of single cell transcriptomics has potentiated our ability to unveil patterns that reflect dynamic cellular processes such as the regulation of gene transcription. In this study, we leverage a broad collection of single cell RNA-seq data to identify the gene partners whose expression is most coordinated with each human and mouse transcription regulator (TR). We assembled 120 human and 103 mouse scRNA-seq datasets from the literature (>28 million cells), constructing a single cell coexpression network for each. We aimed to understand the consistency of TR coexpression profiles across a broad sampling of biological contexts, rather than examine the preservation of context-specific signals. Our workflow therefore explicitly prioritizes the patterns that are most reproducible across cell types. Towards this goal, we characterize the similarity of each TR's coexpression within and across species. We create single cell coexpression rankings for each TR, demonstrating that this aggregated information recovers literature curated targets on par with ChIP-seq data. We then combine the coexpression and ChIP-seq information to identify candidate regulatory interactions supported across methods and species. Finally, we highlight interactions for the important neural TR ASCL1 to demonstrate how our compiled information can be adopted for community use.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012962
  6. Nat Commun. 2025 Apr 24. 16(1): 3855
    The mechanism of YAP/TAZ transactivation and dual targeting for cancer therapy.
    Man Yu, Jingning Wang, Xiao Zhang, Haoran Zhang, Chaoqiang Li, Juebei Li, Jiaming Lin, Jie Zheng, Liu Huang, Yan Li, Shuguo Sun.
      Transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) play key roles in cancers through transcriptional outputs. However, their transactivation mechanisms remain unclear, and effective targeting strategies are lacking. Here, we show that YAP/TAZ possess a hydrophobic transactivation domain (TAD). TAD knockout prevents tumor establishment due to growth defects and enhances immune attack. Mechanistically, TADs facilitate preinitiation complex (PIC) assembly by recruiting the TATA-binding protein-associated factor 4 (TAF4)-dependent TFIID complex and enhance RNA polymerase II (Pol II) elongation through mediator complex subunit 15 (MED15)-dependent mediator recruitment for the expressions of oncogenic/immune-suppressive programs. The synthesized peptide TJ-M11 selectively disrupts TAD interactions with MED15 and TAF4, suppressing tumor growth and sensitizing tumors to immunotherapy. Our findings demonstrate that YAP/TAZ TADs exhibit dual functions in PIC assembly and Pol II elongation via hydrophobic interactions, which represent actionable targets for cancer therapy and combination immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-59309-w
  7. Dev Cell. 2025 Apr 16. pii: S1534-5807(25)00179-0. [Epub ahead of print]
    RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.
    Tsunetoshi Nakatani, Tamas Schauer, Mrinmoy Pal, Andreas Ettinger, Luis Altamirano-Pacheco, Julia Zorn, David M Gilbert, Maria-Elena Torres-Padilla.
      Cells must duplicate their genome before they divide to ensure equal transmission of genetic information. The genome is replicated with a defined temporal order, replication timing (RT), which is cell-type specific and linked to 3D-genome organization. During mammalian development, RT is initially not well defined and becomes progressively consolidated from the 4-cell stage. However, the molecular regulators are unknown. Here, by combining loss-of-function analysis with genome-wide investigation of RT in mouse embryos, we identify Rap1 interacting factor 1 (RIF1) as a regulator of the progressive consolidation of RT. Embryos without RIF1 show DNA replication features of an early, more totipotent state. RIF1 regulates the progressive stratification of RT values and its depletion leads to global RT changes and a more heterogeneous RT program. Developmental RT changes are disentangled from changes in transcription and nuclear organization, specifically nuclear lamina association. Our work provides molecular understanding of replication and genome organization at the beginning of mammalian development.
    Keywords:  RIF1; early mouse embryos; lamina-associated domains; replication fork speed; replication timing; single-cell Repli-seq
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.016
  8. Nat Neurosci. 2025 Apr 21.
    Integrated analysis of molecular atlases unveils modules driving developmental cell subtype specification in the human cortex.
    Patricia R Nano, Elisa Fazzari, Daria Azizad, Antoni Martija, Claudia V Nguyen, Sean Wang, Vanna Giang, Ryan L Kan, Juyoun Yoo, Brittney Wick, Maximilian Haeussler, Aparna Bhaduri.
      Human brain development requires generating diverse cell types, a process explored by single-cell transcriptomics. Through parallel meta-analyses of the human cortex in development (seven datasets) and adulthood (16 datasets), we generated over 500 gene co-expression networks that can describe mechanisms of cortical development, centering on peak stages of neurogenesis. These meta-modules show dynamic cell subtype specificities throughout cortical development, with several developmental meta-modules displaying spatiotemporal expression patterns that allude to potential roles in cell fate specification. We validated the expression of these modules in primary human cortical tissues. These include meta-module 20, a module elevated in FEZF2+ deep layer neurons that includes TSHZ3, a transcription factor associated with neurodevelopmental disorders. Human cortical chimeroid experiments validated that both FEZF2 and TSHZ3 are required to drive module 20 activity and deep layer neuron specification but through distinct modalities. These studies demonstrate how meta-atlases can engender further mechanistic analyses of cortical fate specification.
    DOI:  https://doi.org/10.1038/s41593-025-01933-2
  9. Sci Adv. 2025 Apr 25. 11(17): eads6385
    BRD9 functions as a methylarginine reader to regulate AKT-EZH2 signaling.
    Shasha Yin, Charles Brobbey, Lauren E Ball, Tianmin Fu, Daniel J Sprague, Wenjian Gan.
      Recognition of methylarginine marks by effector proteins ("readers") is a critical link between arginine methylation and various cellular processes. Recently, we identified methylation of AKT1 at arginine-391 (R391), but the reader for this methylation has yet to be characterized. Here, we show that bromodomain-containing protein 9 (BRD9), a reader of acetylated lysine, unexpectedly recognizes methylated R391 of AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA sequencing data show that BRD9 and AKT coregulate a hallmark transcriptional program in part through enhancer of zeste homolog 2 (EZH2)-mediated methylation of histone-3 lysine-27. We also find that inhibitors of BRD9 and EZH2 display synergistic effects on suppression of cell proliferation and tumor growth. Collectively, our study reveals a previously unknown function of BRD9 and a potential therapeutic strategy for cancer treatment by combining BRD9 and EZH2 inhibitors.
    DOI:  https://doi.org/10.1126/sciadv.ads6385
  10. Nat Genet. 2025 Apr 21.
    Transcriptome-wide analysis of differential expression in perturbation atlases.
    Ajay Nadig, Joseph M Replogle, Angela N Pogson, Mukundh Murthy, Steven A McCarroll, Jonathan S Weissman, Elise B Robinson, Luke J O'Connor.
      Single-cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are noisy, and many effects may go undetected. Here we introduce transcriptome-wide analysis of differential expression (TRADE)-a statistical model for the distribution of true differential expression effects that accounts for estimation error appropriately. TRADE estimates the 'transcriptome-wide impact', which quantifies the total effect of a perturbation across the transcriptome. Analyzing several large Perturb-seq datasets, we show that many transcriptional effects remain undetected in standard analyses but emerge in aggregate using TRADE. A typical gene perturbation affects an estimated 45 genes, whereas a typical essential gene affects over 500. We find moderate consistency of perturbation effects across cell types, identify perturbations where transcriptional responses vary qualitatively across dosage levels and clarify the relationship between genetic and transcriptomic correlations across neuropsychiatric disorders.
    DOI:  https://doi.org/10.1038/s41588-025-02169-3
  11. Nature. 2025 Apr 23.
    Human de novo mutation rates from a four-generation pedigree reference.
    David Porubsky, Harriet Dashnow, Thomas A Sasani, Glennis A Logsdon, Pille Hallast, Michelle D Noyes, Zev N Kronenberg, Tom Mokveld, Nidhi Koundinya, Cillian Nolan, Cody J Steely, Andrea Guarracino, Egor Dolzhenko, William T Harvey, William J Rowell, Kirill Grigorev, Thomas J Nicholas, Michael E Goldberg, Keisuke K Oshima, Jiadong Lin, Peter Ebert, W Scott Watkins, Tiffany Y Leung, Vincent C T Hanlon, Sean McGee, Brent S Pedersen, Hannah C Happ, Hyeonsoo Jeong, Katherine M Munson, Kendra Hoekzema, Daniel D Chan, Yanni Wang, Jordan Knuth, Gage H Garcia, Cairbre Fanslow, Christine Lambert, Charles Lee, Joshua D Smith, Shawn Levy, Christopher E Mason, Erik Garrison, Peter M Lansdorp, Deborah W Neklason, Lynn B Jorde, Aaron R Quinlan, Michael A Eberle, Evan E Eichler.
      Understanding the human de novo mutation (DNM) rate requires complete sequence information1. Here using five complementary short-read and long-read sequencing technologies, we phased and assembled more than 95% of each diploid human genome in a four-generation, twenty-eight-member family (CEPH 1463). We estimate 98-206 DNMs per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs. Among male individuals, we find 12.4 de novo Y chromosome events per generation. Short tandem repeats and variable-number tandem repeats are the most mutable, with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 16% of de novo single-nucleotide variants are postzygotic in origin with no paternal bias, including early germline mosaic mutations. We place all this variation in the context of a high-resolution recombination map (~3.4 kb breakpoint resolution) and find no correlation between meiotic crossover and de novo structural variants. These near-telomere-to-telomere familial genomes provide a truth set to understand the most fundamental processes underlying human genetic variation.
    DOI:  https://doi.org/10.1038/s41586-025-08922-2
  12. Oncogenesis. 2025 Apr 24. 14(1): 13
    MYCN and KAT2A form a feedforward loop to drive an oncogenic transcriptional program in neuroblastoma.
    Zhihui Liu, Jason J Hong, Xiyuan Zhang, Carly M Sayers, Wendy Fang, Man Xu, Sydney Loria, Sakereh Maskal, Haiyan Lei, Haitao Wu, Rolf Swenson, Jordan L Meier, Jack F Shern, Carol J Thiele.
      The oncoprotein MYCN drives malignancy in various cancer types, including neuroblastoma (NB). However, our understanding of the mechanisms underlying its transcriptional activity and oncogenic function, as well as effective strategies to target it, remains limited. We discovered that MYCN interacts with the transcriptional coactivator KAT2A, and this interaction significantly contributes to MYCN's activity in NB. Our genome-wide analyses indicate MYCN recruits KAT2A to bind to DNA, thereby transcriptionally regulating genes associated with ribosome biogenesis and RNA processing. Moreover, we identified that MYCN directly activates KAT2A transcription, while KAT2A acetylates MYCN, increasing MYCN protein stability. Consequently, MYCN and KAT2A establish a feedforward loop that effectively regulates global gene expression, governing the malignant NB phenotype. Treatment of NB cells with a KAT2A Proteolysis Targeting Chimera (PROTAC) degrader reduces MYCN protein levels, antagonizes MYCN-mediated gene transcription regulation and suppresses cell proliferation. This study highlights the potential of transcriptional cofactors as viable targets for developing anti-MYCN therapies.
    DOI:  https://doi.org/10.1038/s41389-025-00557-2
  13. Methods Mol Biol. 2025 ;2919 1-18
    In Vitro Assembly of Nucleosomes for Binding/Remodeling Assays.
    Kathleen Diep Tran, Arnob Dutta.
      In order to study the functions and activities of chromatin remodeling enzymes in vitro, it is necessary to be able to reconstitute nucleosomes on DNA templates. In this chapter, we describe procedures for purification of histones from E. coli, formation of octamers, and reconstitution of nucleosomes, which can be further modified by chromatin modifiers. In addition, we describe methods to purify nucleosomes from human cells. Finally, we also describe assays to test binding and remodeling activities of chromatin remodelers.
    Keywords:  Chromatin modifying enzyme; Chromatin remodeler; Histone; Nucleosome
    DOI:  https://doi.org/10.1007/978-1-0716-4486-7_1
  14. Cell Syst. 2025 Apr 15. pii: S2405-4712(25)00099-7. [Epub ahead of print] 101266
    Joint analysis of chromatin accessibility and gene expression in the same single cells reveals cancer-specific regulatory programs.
    Lei Tang, Jinsong Zhang, Yanqiu Shao, Yifan Wei, Yuzhe Li, Kang Tian, Xiang Yan, Changjiang Feng, Qiangfeng Cliff Zhang.
      Biological analyses conducted at the single-cell scale have revealed profound impacts of heterogeneity and plasticity of chromatin states and gene expression on physiology and cancer. Here, we developed Parallel-seq, a technology for simultaneously measuring chromatin accessibility and gene expression in the same single cells. By combining combinatorial cell indexing and droplet overloading, Parallel-seq generates high-quality data in an ultra-high-throughput fashion and at a cost two orders of magnitude lower than alternative technologies (10× Multiome and ISSAAC-seq). We applied Parallel-seq to 40 lung tumor and tumor-adjacent clinical samples and obtained over 200,000 high-quality joint scATAC-and-scRNA profiles. Leveraging this large dataset, we characterized copy-number variations (CNVs) and extrachromosomal circular DNA (eccDNA) heterogeneity in tumor cells, predicted hundreds of thousands of cell-type-specific regulatory events, and identified enhancer mutations affecting tumor progression. Our analyses highlight Parallel-seq's power in investigating epigenetic and genetic factors driving cancer development at the cell-type-specific level and its utility for revealing vulnerable therapeutic targets.
    Keywords:  epigenomics; gene expression regulation; lung cancer; single-cell multiomics
    DOI:  https://doi.org/10.1016/j.cels.2025.101266
  15. Cell. 2025 Apr 15. pii: S0092-8674(25)00396-4. [Epub ahead of print]
    The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.
    Mrinmoy Pal, Tamas Schauer, Adam Burton, Tsunetoshi Nakatani, Federico Pecori, Alicia Hernández-Giménez, Iliya Nadelson, Marc A Marti-Renom, Maria-Elena Torres-Padilla.
      The folding of the genome in the 3D nuclear space is fundamental for regulating all DNA-related processes. The association of the genome with the nuclear lamina into lamina-associated domains (LADs) represents the earliest feature of nuclear organization during development. Here, we performed a gain-of-function screen in mouse embryos to obtain mechanistic insights. We find that perturbations impacting histone H3 modifications, heterochromatin, and histone content are crucial for the establishment of nuclear architecture in zygotes and/or 2-cell-stage embryos. Notably, some perturbations exerted differential effects on zygotes versus 2-cell-stage embryos. Moreover, embryos with disrupted LADs can rebuild nuclear architecture at the 2-cell stage, indicating that the initial establishment of LADs in zygotes might be dispensable for early development. Our findings provide valuable insights into the functional interplay between chromatin and structural components of the nucleus that guide genome-lamina interactions during the earliest developmental stages.
    Keywords:  3D genome organization; LAD; MZT; ZGA; epigenetics; mouse embryo; nuclear architecture
    DOI:  https://doi.org/10.1016/j.cell.2025.03.044
  16. Nat Commun. 2025 Apr 23. 16(1): 3800
    IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies.
    Pablo Domizi, Jolanda Sarno, Astraea Jager, Milton Merchant, Kaithlen Zen B Pacheco, Sean A Yamada-Hunter, Maria Caterina Rotiroti, Yuxuan Liu, Reema Baskar, Warren D Reynolds, Brian J Sworder, Bita Sahaf, Sean C Bendall, Charles G Mullighan, Ash A Alizadeh, Allison B Leahy, Regina M Myers, Bonnie Yates, Hao-Wei Wang, Nirali N Shah, Robbie G Majzner, Crystal L Mackall, Stephan A Grupp, David M Barrett, Elena Sotillo, Kara L Davis.
      Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROSlow B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROSlow cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.
    DOI:  https://doi.org/10.1038/s41467-025-58868-2
  17. Cell Rep. 2025 Apr 20. pii: S2211-1247(25)00368-7. [Epub ahead of print]44(5): 115597
    Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and function.
    Komal Kaushik, Gareth Chapman, Ramachandran Prakasam, Faiza Batool, Maamoon Saleh, Julianna Determan, James E Huettner, Kristen L Kroll.
      Pathogenic mutation of the zinc-finger transcription factor ZNF292 is a recently defined contributor to human neurodevelopmental disorders (NDDs). However, the gene's roles in cortical development and regulatory networks under its control were previously undefined. Here, human stem cell models of ZNF292 deficiency, resembling pathogenic haploinsufficiency, are used to derive cortical inhibitory neuron progenitors and neurons. ZNF292-deficient progenitors undergo precocious differentiation but subsequently exhibit compromised interneuron maturation and function. In progenitors, genome-wide occupancy and transcriptomic analyses identify direct target genes controlling neuronal differentiation and synapse formation that are upregulated upon ZNF292 deficiency. By contrast, deficiency in interneurons compromises ZNF292 genome-wide association with and causes downregulation of direct target genes promoting interneuron maturation and function, including other NDD genes. ZNF292-deficient interneurons also exhibit altered channel activities, elevated GABA responsiveness, and hallmarks of neuronal hyperactivity. Together, the results of this work define neurodevelopmental requirements for ZNF292, some of which may contribute to pathogenic ZNF292 mutation-related NDDs.
    Keywords:  CP: Developmental biology; CP: Neuroscience; autism; cortical interneuron differentiation; cortical neuron; electrophysiological function; genome-wide occupancy; human pluripotent stem cell; neurodevelopmental disorders; transcriptional regulation; zinc-finger transcription factor
    DOI:  https://doi.org/10.1016/j.celrep.2025.115597
  18. iScience. 2025 May 16. 28(5): 112292
    Preparation for mitosis requires gradual CDK1 activation.
    Karen Akopyan, Zhiyu Hao, Arne Lindqvist.
      G2 phase is considered as a time in which cells prepare for the large structural changes in the following mitosis. Starting at completion of DNA replication, CDK1 and PLK1 kinase activities gradually increase throughout G2 phase until reaching levels that initiate mitosis. Here, we use a combination of experiments and a data-driven mathematical model to study the connection between DNA replication and mitosis. We find that gradual activation of mitotic kinases ensures CDK1-dependent transcription of factors required for mitosis. In addition, we find that gradual activation of CDK1 coordinates CDK1 and PLK1 activation. Conversely, shortening G2 phase by WEE1 inhibition leads to mitotic delays, which can be partially rescued by expression of constitutively active PLK1. Our results show a function for slow mitotic kinase activation through G2 phase and suggest a mechanism for how the timing of mitotic entry is linked to preparation for mitosis.
    Keywords:  Cell biology; Functional aspects of cell biology; Mathematical biosciences
    DOI:  https://doi.org/10.1016/j.isci.2025.112292
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