دورية أكاديمية
Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens.
| العنوان: | Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens. |
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| المؤلفون: | Otto JE; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Chemical Biology Program, Harvard University, Cambridge, MA, USA., Ursu O; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Wu AP; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA., Winter EB; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Cuoco MS; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ma S; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Qian K; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA., Michel BC; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA., Buenrostro JD; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Berger B; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA., Regev A; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, UA. Electronic address: aviv.regev.sc@gmail.com., Kadoch C; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Chemical Biology Program, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, UA. Electronic address: cigall_kadoch@dfci.harvard.edu. |
| المصدر: | Molecular cell [Mol Cell] 2023 Apr 20; Vol. 83 (8), pp. 1350-1367.e7. Date of Electronic Publication: 2023 Apr 06. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cambridge Ma : Cell Press Original Publication: Cambridge, Mass. : Cell Press, c1997- |
| مواضيع طبية MeSH: | Chromatin Assembly and Disassembly* , Neoplasms*, Animals ; Humans ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Chromatin/genetics ; Mammals/metabolism |
| مستخلص: | The mammalian SWI/SNF (mSWI/SNF or BAF) family of chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression. The three final-form subcomplexes-cBAF, PBAF, and ncBAF-are distinct in biochemical componentry, chromatin targeting, and roles in disease; however, the contributions of their constituent subunits to gene expression remain incompletely defined. Here, we performed Perturb-seq-based CRISPR-Cas9 knockout screens targeting mSWI/SNF subunits individually and in select combinations, followed by single-cell RNA-seq and SHARE-seq. We uncovered complex-, module-, and subunit-specific contributions to distinct regulatory networks and defined paralog subunit relationships and shifted subcomplex functions upon perturbations. Synergistic, intra-complex genetic interactions between subunits reveal functional redundancy and modularity. Importantly, single-cell subunit perturbation signatures mapped across bulk primary human tumor expression profiles both mirror and predict cBAF loss-of-function status in cancer. Our findings highlight the utility of Perturb-seq to dissect disease-relevant gene regulatory impacts of heterogeneous, multi-component master regulatory complexes. Competing Interests: Declaration of interests C.K. is the Scientific Founder, Scientific Advisor to the Board of Directors, Scientific Advisory Board member, shareholder, and consultant for Foghorn Therapeutics, Inc. (Cambridge, MA); serves on the Scientific Advisory Boards of Nereid Therapeutics, Nested Therapeutics, and Fibrogen, Inc.; and is a consultant for Cell Signaling Technologies and Google Ventures. C.K. is also a member of the Molecular Cell advisory board. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and until July 31, 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and ThermoFisher Scientific. Since August 1, 2020, A.R. has been an employee of Genentech and has equity in Roche. Since May 24, 2021, O.U. has been an employee of Genentech and has equity in Roche. J.E.O. is an employee and equity holder of Flagship Labs 84, Inc. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| معلومات مُعتمدة: | DP2 CA195762 United States CA NCI NIH HHS; U01 CA250554 United States CA NCI NIH HHS; United States HHMI Howard Hughes Medical Institute |
| فهرسة مساهمة: | Keywords: ATAC-seq; ATP-dependent chromatin remodeling; BAF complex; Perturb-seq; SHARE-Seq; cancer; chromatin accessibility; gene expression; mammalian SWI/SNF complexes; pediatric cancer; rare diseases |
| المشرفين على المادة: | 0 (Chromosomal Proteins, Non-Histone) 0 (Transcription Factors) 0 (Chromatin) |
| تواريخ الأحداث: | Date Created: 20230407 Date Completed: 20230425 Latest Revision: 20230502 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.molcel.2023.03.013 |
| PMID: | 37028419 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1097-4164 |
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| DOI: | 10.1016/j.molcel.2023.03.013 |