HNF4A is required to specify glucocorticoid action in the liver
HNF4A is required to specify glucocorticoid action in the liver
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DOI：
10.1101/2021.04.10.438998
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发表时间：
2021-04
期刊：
影响因子：
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通讯作者：
A. L. Hunter;T. Poolman;Donghwan Kim;F. Gonzalez;D. Bechtold;A. Loudon;M. Iqbal;D. Ray
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文献类型：
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作者：
A. L. Hunter;T. Poolman;Donghwan Kim;F. Gonzalez;D. Bechtold;A. Loudon;M. Iqbal;D. Ray
糖皮质激素受体(GR)是一种核激素受体，在能量代谢和炎症反应的调节中起关键作用。GR的作用高度依赖于细胞类型和环境。在这里，我们论证了肝脏谱系决定因子肝细胞核因子4A(HNF4a)在确定GR作用的肝脏特异性方面的必要性。在正常小鼠肝脏中，HNF4基序位于糖皮质激素反应元件(GRE)附近，位于开放染色质区域内的GR结合部位。在没有HNF4a的情况下，肝脏GR池被重塑，GR募集的损失和增加都很明显。丢失的位点以HNF4基序和弱GRE基序为特征。获得的位点以强烈的GRE基序为特征，通常显示GR在非肝脏组织中的募集。HNF4a缺失型肝脏对糖皮质激素治疗的转录反应改变的证据进一步证明了这些HNF4a调节的GR位点的功能重要性。
The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. 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.