Departments of Genome Sciences and Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA.
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA.
Cell Rep. 2020 May 26;31(8):107676. doi: 10.1016/j.celrep.2020.107676.
The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.
人类基因组编码了数百万个调控元件，其中只有一小部分在特定细胞类型中具有活性。关于染色质重塑因子对调控 DNA 景观的全局影响，以及这种影响如何转化为基因表达，我们知之甚少。我们使用精确的基因组工程技术，在肺腺癌细胞中重新激活了人类 SWI/SNF 染色质重塑复合物的核心 ATP 酶 SMARCA4 的纯合失活。在这里，我们结合了 DNase I 超敏性、组蛋白修饰和转录谱分析，结果表明，SMARCA4 极大地增加了全基因组可及染色质位点的数量和幅度，主要是通过揭示低调控因子占据的位点。相比之下，转录变化主要集中在明确界定的重塑域内，其中特定基因的表达受到远端元件激活和启动子染色质结构的双重控制。我们的研究结果提供了一个视角，即通过调控 DNA，全局染色质重塑活性如何转化为基因表达。
