HNF4A modulates glucocorticoid action in the liver.
HNF4A modulates glucocorticoid action in the liver.
复制标题
DOI：
10.1016/j.celrep.2022.110697
复制
发表时间：
2022-04-19
期刊：
影响因子：
8.8
通讯作者：
Ray, David W.
中科院分区：
文献类型：
--
作者：
Hunter, A. Louise;Poolman, Toryn M.;Kim, Donghwan;Gonzalez, Frank J.;Bechtold, David A.;Loudon, Andrew S., I;Iqbal, Mudassar;Ray, David W.
糖皮质激素受体（GR）是调节能量代谢和炎症的关键核受体。GR的作用取决于细胞类型和环境。在这里，我们证明了肝谱系决定因子肝细胞核因子4A（HNF 4A）在定义GR作用的肝脏特异性中的作用。在小鼠肝脏中，HNF4A基序位于开放染色质区域内糖皮质激素反应元件（GRE）的GR结合位点附近。在没有HNF4A的情况下，肝脏GR顺式组被重塑，GR募集的损失和获得是明显的。在HNF 4A标记位点的染色质可及性的丧失与弱GRE基序的GR结合的丧失相关。GR结合和染色质可及性在以强GRE基序为特征的位点获得，这表明GR在非肝组织中募集。这些HNF4A调节的GR位点的功能重要性由Hnf4a缺失肝脏中对糖皮质激素治疗的改变的转录应答指示。在小鼠肝脏中，核因子HNF 4A标记GR结合位点的群体HNF 4A的缺失导致HNF 4A标记位点的GR结合丧失在HNF 4A缺失的情况下，GR结合在肝脏中通常不结合的反应元件上，同时在HNF 4A依赖的GR位点处染色质可及性被重塑糖皮质激素受体（GR）的作用依赖于细胞类型和细胞状态。Hunter等人显示，在小鼠肝脏中，谱系决定因子HNF4A是重要的指定全基因组的GR的结合概况。删除HNF4A重塑染色质的可及性和GR结合在HNF4A标记的网站。
The glucocorticoid receptor (GR) is a nuclear receptor critical to the regulation of energy metabolism and inflammation. The actions of GR are dependent on cell type and context. Here, we demonstrate the role of liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver specificity of GR action. In mouse liver, the HNF4A motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodeled, with loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites associates with loss of GR binding at weak GRE motifs. GR binding and chromatin accessibility are gained at sites characterized by strong GRE motifs, which show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is indicated by an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver. In mouse liver, nuclear factor HNF4A marks a population of GR binding sites Deletion of Hnf4a results in loss of GR binding at HNF4A-marked sites In the absence of HNF4A, GR binds at response elements not typically bound in liver Chromatin accessibility is concurrently remodeled at HNF4A-dependent GR sites The action of the glucocorticoid receptor (GR) is dependent upon cell type and cell state. Hunter et al. show that, in mouse liver, the lineage-determining factor HNF4A is important for specifying the genome-wide binding profile of GR. Deletion of Hnf4a remodels chromatin accessibility and GR binding at HNF4A-marked sites.
登录
查看更多内容
影响因子：
--
作者：
Briggs, Peter;Hunter, A Louise;Iqbal, Mudassar
通讯作者：
Iqbal, Mudassar
影响因子：
16.6
作者：
Armour SM;Remsberg JR;Damle M;Sidoli S;Ho WY;Li Z;Garcia BA;Lazar MA
通讯作者：
Lazar MA
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
30.8
作者：
John S;Sabo PJ;Thurman RE;Sung MH;Biddie SC;Johnson TA;Hager GL;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
影响因子：
9.3
作者：
D'lppolito, Anthony M.;McDowell, Ian C.;Reddy, Timothy E.
通讯作者：
Reddy, Timothy E.