CRISPR screen decodes SWI/SNF chromatin remodeling complex assembly

Article Article scientifique Article CRISPR screen decodes SWI/SNF chromatin remodeling complex assembly eng 2025-05-30 2025-05-30 author Schwaemmle Hanna 0000-0002-1114-3694 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. 965710 Département de médecine génétique et développement (GEDEV) author Soldati Hadrien Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 706745 Département de médecine génétique et développement (GEDEV) author Lykoskoufis Nikolaos Michail Rafail 0000-0001-6751-7010 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 776530 author Docquier Mylene Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. 513819 Génétique programme prioritaire (GENPP) author Hainard Alexandre 0009-0006-7403-3261 Proteomics Core Facility, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 635700 Services communs de la faculté de médecine (SCMU) author Braun Simon 0000-0003-2622-9914 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland. simon.braun@unige.ch.,Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. simon.braun@unige.ch. 930774 Département de médecine génétique et développement (GEDEV) 5011 10.1038/s41467-025-60424-x 40447637 2041-1723 PMC12125367 https://www.nature.com/articles/s41467-025-60424-x The SWI/SNF (or BAF) complex is an essential chromatin remodeler, which is frequently mutated in cancer and neurodevelopmental disorders. These are often heterozygous loss-of-function mutations, indicating a dosage-sensitive role for SWI/SNF subunits. However, the molecular mechanisms regulating SWI/SNF subunit dosage to ensure complex assembly remain largely unexplored. We performed a CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identified Mlf2 and Rbm15 as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, promotes SWI/SNF assembly and binding to chromatin. Rapid degradation of MLF2 reduces chromatin accessibility at sites that depend on high levels of SWI/SNF binding to maintain open chromatin. Next, we find that RBM15, part of the m6 A writer complex, controls m6 A modifications on specific SWI/SNF mRNAs to regulate subunit protein levels. Misregulation of m6 A methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling. Animals Mice Chromatin Assembly and Disassembly / genetics Chromosomal Proteins, Non-Histone / metabolism Chromosomal Proteins, Non-Histone / genetics Transcription Factors / metabolism Transcription Factors / genetics Chromatin / metabolism Chromatin / genetics RNA-Binding Proteins / metabolism RNA-Binding Proteins / genetics Mouse Embryonic Stem Cells / metabolism CRISPR-Cas Systems Humans Clustered Regularly Interspaced Short Palindromic Repeats Dewey 590 Dewey 576.5 Swiss National Science Foundation Epigenome editing to study chromatin remodeling during brain development 194305 CH Careers 135 Département de médecine génétique et développement 21D 23 Institut de génétique et de génomique 0DH false 1357 Régulation de la chromatine dans le développement du cerveau 1031 https://github.com/NLykoskoufis/BraunLabPipeline https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE268206 https://www.ebi.ac.uk/pride/archive/projects/PXD054392 https://www.ebi.ac.uk/pride/archive/projects/PXD061408 Nature communications 16 1 12da2d4d-1a94-4c29-83c0-68776f20141b Article (Published version) Public Article_scientifique_from_unpaywall.pdf 5630070 application/pdf CC BY-4.0 7b56321c5d3a564fe678586aec8b31e64946a1b2c1f842907269e64a8bcf4000 5d3bb526-0c04-42a9-b755-d6ec5e5f57f1 Appendix Public 41467_2025_60424_MOESM1_ESM.pdf 10632334 application/pdf a506b5d4563357a707cfdbbfb80f8ac160a3ea28cd3b80815130ddfb31ff4af1 74732bf0-a0dc-4494-b57d-00ad47d7fba1 Appendix Public 41467_2025_60424_MOESM2_ESM.pdf 130603 application/pdf 58d1af0837122390f8e55c443fe00c711a578f6317ee406618a578300b01efba fa3ac752-78ce-481e-bf8a-b57d9de0225a Appendix Public 41467_2025_60424_MOESM3_ESM.xlsx 2281578 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 8e9a25e6f82ccc2d5ed34bcb82ad297b0f1bb49c748a38076174e4d6b3fdb321 12ce60c0-3b78-41b0-868a-a57a6a2e8326 Appendix Public 41467_2025_60424_MOESM4_ESM.xlsx 16987435 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 89ad7da289ea7fc098fb29c7a180d048fb002b036f46391aa182ffd38efa989c ca14cd3d-b944-4caa-9e3e-50d84a97b753 Appendix Public 41467_2025_60424_MOESM5_ESM.xlsx 22834931 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 8aa70e99a8b998b9096d34f54b1778e2cb216f91dfbc8d5a1f4538677f8204dc 28e34a89-5089-4778-b540-6a5b5cd169ac Appendix Public 41467_2025_60424_MOESM6_ESM.xlsx 15049138 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 3298151bb5ae11284e4edae963a01744f3c266fb03f0b36eb04d626b7ed68f2c fbb4dd34-301d-41d5-a27c-a37e548fe15e Appendix Public 41467_2025_60424_MOESM7_ESM.xlsx 24869108 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet a1e3c9de018a5ea2f35a8ec04328d78574a07e99d85b0b446c1991d08757c9ff 277d7e56-8629-4cda-8476-8077fdfd22ee Appendix Public 41467_2025_60424_MOESM8_ESM.xlsx 14402 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 1ce6629b1242cebabc52ee14d1ecc56b9271e03890c08ae0e8a0b25a80c8f9e2 92c6fa74-6e82-41ba-b516-2d1478cb202c Appendix Public 41467_2025_60424_MOESM9_ESM.pdf 5586867 application/pdf cd13e96960d0a22bc85fca50886fd01068b0d45680709fab84a10c1d59513679 0b5da2e5-7792-47b6-8707-8244465d1a12 Appendix Public 41467_2025_60424_MOESM10_ESM.pdf 1773580 application/pdf be443e4c8448683ba4c570e88f44bfd49531151af50fa3cd8d05e5d86f8ce75b 4d23f7d9-1505-42f5-a227-e29db44d719e Appendix Public 41467_2025_60424_MOESM11_ESM.xlsx 16645332 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 5eb4065fbe217c17f410a2f09b22a2d93e28abdff4ffdff225d8b28e36761009 openAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Centres et instituts / Institut de génétique et de génomique

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