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.
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染色质的可获得性是ARID1A突变癌症中SWI/SNF亚单位合成致死性的基础。
DOI：
10.7554/elife.30506
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发表时间：
2017-10-02
期刊：
影响因子：
7.7
通讯作者：
Hargreaves DC
中科院分区：
文献类型：
--
作者：
Kelso TWR;Porter DK;Amaral ML;Shokhirev MN;Benner C;Hargreaves DC
ARID1A是SWI/SNF染色质重塑复合体的一个亚单位，在癌症中经常发生突变。其同系物ARID1B的缺陷对ARID1A突变具有综合致命性。然而，这些同系物之间的功能关系还没有被探索。在这里，我们使用ATAC-SEQ、全基因组组蛋白修饰图谱和表达分析来检测缺乏一种或两种干旱蛋白的结直肠癌细胞。我们发现ARID1A在维持染色质在增强子上的可及性方面起主导作用，而ARID1B的贡献只有在ARID1A突变的背景下才明显。可及性的变化预示着表达的变化，并与H3K4me和H3K27ac标记的丢失、核小体间距和转录因子结合相关，特别是在生长途径基因包括MET。我们发现，在ARID1A突变的卵巢癌细胞中，ARID1B基因敲除会导致类似的增强子结构丢失，这表明这是ARID1A和ARID1B之间合成杀伤力背后的一种保守功能。
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.