STAG2 mutations regulate 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme.

Autor:	Xu W; Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve School of Medicine, Cleveland, Ohio, USA; The Biomedical Sciences Training Program, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Kim JS; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia, USA., Yang T; Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve School of Medicine, Cleveland, Ohio, USA; The Biomedical Sciences Training Program, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Ya A; MD/PhD Program, Georgetown University School of Medicine, Washington, District of Columbia, USA; Tumor Biology Training Program, Georgetown University School of Medicine, Washington, District of Columbia, USA., Sadzewicz L; Institute for Genome Sciences, University of Maryland, Baltimore, Maryland, USA., Tallon L; Institute for Genome Sciences, University of Maryland, Baltimore, Maryland, USA., Harris BT; Departments of Neurology and Pathology, Georgetown University School of Medicine, Washington, District of Columbia, USA., Sarkaria J; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Jin F; Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve School of Medicine, Cleveland, Ohio, USA; Department of Computer and Data Sciences, Department of Population and Quantitative Health Sciences, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA. Electronic address: fxj45@case.edu., Waldman T; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia, USA. Electronic address: waldmant@georgetown.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Jun; Vol. 300 (6), pp. 107341. Date of Electronic Publication: 2024 May 03.
DOI:	10.1016/j.jbc.2024.107341
Abstrakt:	Inactivating mutations of genes encoding the cohesin complex are common in a wide range of human cancers. STAG2 is the most commonly mutated subunit. Here we report the impact of stable correction of endogenous, naturally occurring STAG2 mutations on gene expression, 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme (GBM). In two GBM cell lines, correction of their STAG2 mutations significantly altered the expression of ∼10% of all expressed genes. Virtually all the most highly regulated genes were negatively regulated by STAG2 (i.e., expressed higher in STAG2-mutant cells), and one of them-HEPH-was regulated by STAG2 in uncultured GBM tumors as well. While STAG2 correction had little effect on large-scale features of 3D genome organization (A/B compartments, TADs), STAG2 correction did alter thousands of individual chromatin loops, some of which controlled the expression of adjacent genes. Loops specific to STAG2-mutant cells, which were regulated by STAG1-containing cohesin complexes, were very large, supporting prior findings that STAG1-containing cohesin complexes have greater loop extrusion processivity than STAG2-containing cohesin complexes and suggesting that long loops may be a general feature of STAG2-mutant cancers. Finally, STAG2 mutation activated Polycomb activity leading to increased H3K27me3 marks, identifying Polycomb signaling as a potential target for therapeutic intervention in STAG2-mutant GBM tumors. Together, these findings illuminate the landscape of STAG2-regulated genes, A/B compartments, chromatin loops, and pathways in GBM, providing important clues into the largely still unknown mechanism of STAG2 tumor suppression. Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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