HNF4A is required to specify glucocorticoid action in the liver - ATACseq. HNF4A is required to specify glucocorticoid action in the liver - ATACseq

The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR have been shown to be highly dependent on context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining tissue-specificity of GR action. In normal liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin, as supported by this ATAC-seq data. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

糖皮质激素受体（glucocorticoid receptor, GR）是一类核激素受体，在能量代谢与炎症反应的调控中发挥关键作用。已有研究表明，GR的生物学活性高度依赖于组织细胞背景。本研究证实，肝脏谱系决定性因子肝细胞核因子4A（hepatocyte nuclear factor 4A, HNF4A）是定义GR组织特异性作用所必需的调控因子。在正常肝脏中，本研究的ATAC-seq数据显示，开放染色质区域内的GR结合位点处，HNF4结合基序紧邻糖皮质激素反应元件（glucocorticoid response element, GRE）。当HNF4A缺失时，肝脏GR的全基因组结合位点谱会发生重塑，GR的招募既出现丢失也出现获得。丢失的结合位点以HNF4基序与弱效GRE基序为特征；而获得的结合位点则以强效GRE基序为特征，且通常在非肝脏组织中可检测到GR招募现象。通过Hnf4a敲除肝脏中糖皮质激素处理后转录应答发生改变的实验证据，本研究进一步证实了这些受HNF4A调控的GR结合位点的功能重要性。