PDF(Pubmed)
Abstract：
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.
摘要：
编码粘附素复合物的基因的失活突变在广泛的人类癌症中是常见的。STAG2是最常见的突变亚基。在这里，我们报告了内生稳定修正的影响，天然发生的STAG2基因表达突变，3D基因组组织，染色质环,多形性胶质母细胞瘤（GBM）中的多梳信号传导。在两个GBM细胞系中，纠正他们的STAG2突变显著改变了所有表达基因的10%的表达。几乎所有高度调控的基因都受到STAG2的负调控(即，在STAG2突变细胞中表达更高)，其中之一-HEPH-在未培养的GBM肿瘤中也受到STAG2的调节。虽然STAG2校正对3D基因组组织的大规模特征影响不大(A/B区室，TAD),STAG2校正确实改变了数千个单独的染色质环，其中一些控制相邻基因的表达。特异于STAG2突变细胞的环，受含有STAG1的粘附蛋白复合物的调节，非常大，支持先前的发现，即含有STAG1的粘附蛋白复合物比含有STAG2的粘附蛋白复合物具有更大的环挤压持续能力，并表明长环可能是STAG2突变癌症的一般特征。最后,STAG2突变激活Polycomb活性，导致H3K27me3标记增加，鉴定Polycomb信号传导是STAG2突变型GBM肿瘤治疗干预的潜在靶标。一起,这些发现阐明了STAG2调节基因的景观，A/B舱,染色质环,以及GBM中的路径，为STAG2肿瘤抑制机制在很大程度上仍然未知提供了重要线索。
