The KRAB Zinc Finger Protein RSL1 Regulates Sex- and Tissue-Specific Promoter Methylation and Dynamic Hormone-Responsive Chromatin Configuration
The KRAB Zinc Finger Protein RSL1 Regulates Sex- and Tissue-Specific Promoter Methylation and Dynamic Hormone-Responsive Chromatin Configuration
复制标题
DOI：
10.1128/mcb.00615-12
复制
发表时间：
2012-09-01
影响因子：
5.3
通讯作者：
Robins, Diane M.
中科院分区：
文献类型：
--
作者：
Krebs, Christopher J.;Schultz, David C.;Robins, Diane M.
哺乳动物基因组中编码有400多种与kruppel相关的盒锌指蛋白（krabzfps）。虽然KRAB-ZFPs在体外强烈抑制转录，但对其在体内的生物学功能或基因靶点知之甚少。性别限制调节因子1 （Rsl1）是最早被赋予生理作用的KRAB-Zfp基因之一，它能加强肝脏基因的性别偏倚表达，尤其是小鼠性别限制蛋白（Slp），它提供了KRAB-Zfp功能的体内报告基因。生长激素（GH）和雄激素分别诱导雄性肝脏和肾脏发生Slp。在肝脏而不是肾脏中，Rsl1基因型与Slp启动子中CpG二核苷酸的甲基化相关，该启动子在青春期去甲基化。在体外和体内，RSL1结合在Slp启动子上游2kb处，在一个包含STAT5b应答元件的增强子内。染色质免疫沉淀（ChIP）实验表明，RSL1将体外KRAB作用的协同抑制因子KAP1/TRIM28招募到该增强子上。Slp诱导需要染色质中STAT5b的快速循环。值得注意的是，RSL1同时与STAT5b相邻结合，其相互结合模式限制了激素反应。这些实验证明了激素激活因子STAT5b和KRAB-ZFP抑制因子之间令人惊讶的动态相互作用，并为KRAB-ZFP表观遗传机制提供了独特的见解。
Over 400 Kruppel-associated box zinc finger proteins (KRAB-ZFPs) are encoded in mammalian genomes. While KRAB-ZFPs strongly repress transcription in vitro, little is known about their biological function or gene targets in vivo. Regulator of sex limitation 1 (Rsl1), one of the first KRAB-Zfp genes assigned a physiological role, accentuates sex-biased liver gene expression, most dramatically for mouse sex-limited protein (Slp), which provides an in vivo reporter of KRAB-ZFP function. Slp is induced in males in the liver and kidney by growth hormone (GH) and androgen, respectively. In the liver but not kidney, the Rsl1 genotype correlates with methylation of a CpG dinucleotide in the Slp promoter that is demethylated at puberty. RSL1 binds 2 kb upstream of the Slp promoter, both in vitro and in vivo, within an enhancer containing response elements for STAT5b. Chromatin immunoprecipitation (ChIP) assays demonstrate that RSL1 recruits KAP1/TRIM28, the corepressor for KRAB action in vitro, to this enhancer. Slp induction requires rapid cycling of STAT5b in chromatin. Remarkably, RSL1 simultaneously binds adjacent to STAT5b with a reciprocal binding pattern that limits hormonal response. These experiments demonstrate a surprisingly dynamic interplay between a hormonal activator, STAT5b, and a KRAB-ZFP repressor and provide unique insights into KRAB-ZFP epigenetic mechanisms.