Genome-wide Regulatory Roles of the C2H2-type Zinc Finger Protein ZNF764 on the Glucocorticoid Receptor.
Genome-wide Regulatory Roles of the C2H2-type Zinc Finger Protein ZNF764 on the Glucocorticoid Receptor.
复制标题
C2H2型锌指蛋白ZnF764在糖皮质激素受体上的全基因组调节作用。
DOI：
10.1038/srep41598
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发表时间：
2017-01-31
影响因子：
4.6
通讯作者：
Kino T
中科院分区：
文献类型：
--
作者：
Fadda A;Syed N;Mackeh R;Papadopoulou A;Suzuki S;Jithesh PV;Kino T
C2H2 型锌指蛋白 ZNF764 充当多种类固醇激素受体的增强子，该基因的单倍体不足可能是组织对多种类固醇激素（包括在 16p11.2 微缺失患者中观察到的糖皮质激素）产生抵抗的原因。我们以 HeLa 细胞为模型系统，研究了 ZNF764 对糖皮质激素受体 (GR) 的全基因组调控作用。 ZNF764 和 GR 结合位点在各种基因组特征中表现出相似的分布。它们主要位于距附近基因转录起始位点 50-500kb 左右的位置，并且彼此紧密定位，其中约 37% 重叠。 ZNF764 对 GR 结合和随后的 mRNA 表达表现出不同的开/关效应：一些基因高度依赖于 ZNF764 的存在/不存在，但其他基因则不然。通路分析显示这 3 个基因组参与不同的细胞活动。 ZNF764 通过其 KRAB 结构域与配体结合结构域处的 GR 发生物理相互作用，并且其与 GR 和锌指结构域的物理相互作用似乎是 ZNF764 调节 GR 转录活性所必需的。因此，ZNF764 是一种辅助因子，通过改变糖皮质激素反应基因上的 GR 结合和转录活性，将 GR 转录活性导向特定的生物途径。
The C2H2-type zinc finger protein ZNF764 acts as an enhancer for several steroid hormone receptors, and haploinsufficiency of this gene may be responsible for tissue resistance to multiple steroid hormones including glucocorticoids observed in a patient with 16p11.2 microdeletion. We examined genome-wide regulatory actions of ZNF764 on the glucocorticoid receptor (GR) in HeLa cells as a model system. ZNF764- and GR-binding sites demonstrated similar distribution in various genomic features. They positioned predominantly around 50–500 kbs from the transcription start sites of their nearby genes, and were closely localized with each other, overlapping in ~37% of them. ZNF764 demonstrated differential on/off effects on GR-binding and subsequent mRNA expression: some genes were highly dependent on the presence/absence of ZNF764, but others were not. Pathway analysis revealed that these 3 gene groups were involved in distinct cellular activities. ZNF764 physically interacted with GR at ligand-binding domain through its KRAB domain, and both its physical interaction to GR and zinc finger domain appear to be required for ZNF764 to regulate GR transcriptional activity. Thus, ZNF764 is a cofactor directing GR transcriptional activity toward specific biologic pathways by changing GR binding and transcriptional activity on the glucocorticoid-responsive genes.