Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers
Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers
复制标题
染色质可及性是ARID 1A突变型癌症中SWI/SNF亚基合成致死性的基础
DOI：
10.7554/elife.30506.001
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发表时间：
2017-10-02
期刊：
影响因子：
7.7
通讯作者：
Hargreaves, Diana C.
中科院分区：
文献类型：
--
作者：
Kelso, Timothy W. R.;Porter, Devin K.;Hargreaves, Diana C.
ARID 1A是SWI/SNF染色质重塑复合物的一个亚基，在癌症中经常发生突变。其同源物ARID 1B的缺陷与ARID 1A突变是合成致死的。然而，这些同系物之间的功能关系尚未得到探讨。在这里，我们使用ATAC-seq、全基因组蛋白修饰图谱和表达分析来检查缺乏一种或两种ARID蛋白的结直肠癌细胞。我们发现，ARID 1A在维持增强子处染色质可及性方面具有主导作用，而ARID 1B的贡献仅在ARID 1A突变的情况下是明显的。可及性的变化可预测表达的变化，并与H3 K4 me和H3 K27 ac标记、核小体间距和转录因子结合的丢失相关，特别是在包括MET在内的生长途径基因处。我们发现ARID 1A突变卵巢癌细胞中ARID 1B敲低导致增强子结构的类似损失，表明这是ARID 1A和ARID 1B之间合成致死性的保守功能。
ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here, we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.