Coordinated Regulation of Retinoic Acid Signaling Pathway by KDM5B and Polycomb Repressive Complex 2
Coordinated Regulation of Retinoic Acid Signaling Pathway by KDM5B and Polycomb Repressive Complex 2
复制标题
DOI：
10.1002/jcb.24807
复制
发表时间：
2014-09
影响因子：
4
通讯作者：
Yu Zhang;Jing Liang;Qian Li
中科院分区：
文献类型：
--
作者：
Yu Zhang;Jing Liang;Qian Li
Polycomb 抑制复合物 2 (PRC2) 是许多生物过程中关键的表观遗传调节因子，包括细胞身份的维持、干细胞自我更新、分化，以及在人类癌症和疾病中经常观察到 PRC2 的失调。在这里，我们报道KDM5B（PLU-1/JARID1B）是Jumonji家族的一种组蛋白赖氨酸去甲基化酶，与PRC2结合并与PRC2共定位于核体中，它们的物理结合依赖于KDM5B和PRC2的SUZ12成分之间的直接相互作用。有趣的是，KDM5B 和 PRC2 的共存在视黄酸 (RA) 反应基因上保守的顺式调控 DNA 元件中得到证实。转录读数和体外下拉实验表明，KDM5B 是 RA 信号转导的重要共激活子，但不是共抑制子，并且 KDM5B 的 JMJC 结构域和视黄酸受体 α (RARα) 之间的界面对于 RA 介导的基因表达至关重要。详细的染色质免疫沉淀分析揭示了 KDM5B 通过解耦 H3K4me3 去甲基化和 PRC2 拮抗活性对 RA 诱导的基因激活的双相效应，解决了这个看似矛盾的问题。这些结果表明 KDM5B 和 PRC2 以合作和协调的方式调节 RA 信号级联。 J.细胞。生物化学。 115：1528–1538，2014 年。© 2014 Wiley 期刊公司。
Polycomb repressive complex 2 (PRC2) is a critical epigenetic regulator in many biological processes, including maintenance of cell identity, stem cell self‐renewal, differentiation, and deregulation of PRC2 is often observed in human cancers and diseases. Here we report that KDM5B (PLU‐1/JARID1B), a histone lysine demethylase of Jumonji family, associates with PRC2 and colocalizes with PRC2 in nuclear bodies, and their physical association is dependent on direct interaction between KDM5B and the SUZ12 component of PRC2. Interestingly, co‐occupancy of KDM5B and PRC2 was evidenced at the conserved cis‐regulatory DNA element on retinoic acid (RA) responsive genes. Transcription readout and in vitro pull‐down experiments suggest that KDM5B is an essential co‐activator, but not a co‐repressor, for the RA signaling, and the interface between KDM5B's JMJC domain and retinoic acid receptor α (RARα) is crucial for RA‐mediated gene expression. Detailed chromatin immunoprecipitation assays addressed the seemingly paradox by revealing a biphasic effect of KDM5B on RA‐induced gene activation through decoupled H3K4me3 demethylation and PRC2‐antagonizing activities. These results demonstrate that KDM5B and PRC2 regulate RA signaling cascade in a cooperative and orchestrated fashion. J. Cell. Biochem. 115: 1528–1538, 2014. © 2014 Wiley Periodicals, Inc.