Lin Chia-Hui, Li Bing, Swanson Selene, Zhang Ying, Florens Laurence, Washburn Michael P, Abmayr Susan M, Workman Jerry L
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Mol Cell. 2008 Dec 5;32(5):696-706. doi: 10.1016/j.molcel.2008.11.008.
Recent discoveries of histone demethylases demonstrate that histone methylation is reversible. However, mechanisms governing the targeting and regulation of histone demethylation remain elusive. Here we report that a Drosophila melanogaster JmjC domain-containing protein, dKDM4A, is a histone H3K36 demethylase. dKDM4A specifically demethylates H3K36me2 and H3K36me3 both in vitro and in vivo. Affinity purification and mass spectrometry analysis revealed that heterochromatin protein 1a (HP1a) associates with dKDMA4A. We found that the chromo shadow domain of HP1a and a HP1-interacting motif of dKDM4A are responsible for this interaction. HP1a stimulates the histone H3K36 demethylation activity of dKDM4A, and this stimulation depends on the H3K9me-binding motif of HP1a. Finally, we provide in vivo evidence suggesting that HP1a and dKDM4A interact with each other and that loss of HP1a leads to an increased level of histone H3K36me3. Collectively, these results suggest a function of HP1a in transcription facilitating H3K36 demethylation at transcribed and/or heterochromatin regions.
近期对组蛋白去甲基化酶的发现表明，组蛋白甲基化是可逆的。然而，调控组蛋白去甲基化靶向作用和调节机制仍不清楚。在此，我们报道一种含有JmjC结构域的果蝇蛋白dKDM4A是一种组蛋白H3K36去甲基化酶。dKDM4A在体外和体内均能特异性地使H3K36me2和H3K36me3去甲基化。亲和纯化和质谱分析显示，异染色质蛋白1a（HP1a）与dKDMA4A相互作用。我们发现，HP1a的染色体阴影结构域和dKDM4A的一个HP1相互作用基序介导了这种相互作用。HP1a刺激dKDM4A的组蛋白H3K36去甲基化活性，且这种刺激依赖于HP1a的H3K9me结合基序。最后，我们提供了体内证据，表明HP1a和dKDM4A相互作用，且HP1a缺失会导致组蛋白H3K36me3水平升高。总的来说，这些结果表明HP1a在转录过程中具有促进转录区域和/或异染色质区域H3K36去甲基化的功能。
