Lee Min Gyu, Norman Jessica, Shilatifard Ali, Shiekhattar Ramin
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Cell. 2007 Mar 9;128(5):877-87. doi: 10.1016/j.cell.2007.02.004. Epub 2007 Feb 22.
Histone methylation is a posttranslational modification regulating chromatin structure and gene regulation. BHC110/LSD1 was the first histone demethylase described to reverse dimethyl histone H3 lysine 4 (H3K4). Here we show that JARID1d, a JmjC-domain-containing protein, specifically demethylates trimethyl H3K4. Detailed mapping analysis revealed that besides the JmjC domain, the BRIGHT and zinc-finger-like C(5)HC(2) domains are required for maximum catalytic activity. Importantly, isolation of native JARID1d complexes from human cells revealed the association of the demethylase with a polycomb-like protein Ring6a/MBLR. Ring6a/MBLR not only directly interacts with JARID1d but also regulates its enzymatic activity. We show that JARID1d and Ring6a occupy human Engrailed 2 gene and regulate its expression and H3K4 methylation levels. Depletion of JARID1d enhanced recruitment of the chromatin remodeling complex, NURF, and the basal transcription machinery near the transcriptional start site, revealing a role for JARID1d in regulation of transcriptional initiation through H3K4 demethylation.
组蛋白甲基化是一种调节染色质结构和基因调控的翻译后修饰。BHC110/LSD1是首个被描述可使二甲基化组蛋白H3赖氨酸4（H3K4）发生去甲基化的组蛋白去甲基化酶。在此我们表明，含JmjC结构域的蛋白JARID1d可特异性地使三甲基化H3K4发生去甲基化。详细的定位分析显示，除JmjC结构域外，BRIGHT结构域和锌指样C(5)HC(2)结构域对于最大催化活性也是必需的。重要的是，从人细胞中分离天然JARID1d复合物揭示了该去甲基化酶与一种类多梳蛋白Ring6a/MBLR的关联。Ring6a/MBLR不仅直接与JARID1d相互作用，还调节其酶活性。我们表明，JARID1d和Ring6a占据人同源异型基因2（Engrailed 2）基因并调节其表达及H3K4甲基化水平。JARID1d的缺失增强了染色质重塑复合物NURF以及转录起始位点附近基础转录机制的募集，揭示了JARID1d在通过H3K4去甲基化调控转录起始中的作用。
