Laurent Benoit, Ruitu Lv, Murn Jernej, Hempel Kristina, Ferrao Ryan, Xiang Yang, Liu Shichong, Garcia Benjamin A, Wu Hao, Wu Feizhen, Steen Hanno, Shi Yang
Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston MA, 02115, USA.
Department of Biochemistry and Epigenetics Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Mol Cell. 2015 Mar 19;57(6):957-970. doi: 10.1016/j.molcel.2015.01.010. Epub 2015 Feb 12.
Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.
据报道，赖氨酸特异性去甲基化酶1（LSD1）分别通过介导组蛋白H3K4me1/2和H3K9me1/2去甲基化来抑制和激活转录。这种双重底物特异性的分子机制尚不清楚。在此，我们报道LSD1的一种同工型LSD1+8a不具有去甲基化H3K4me2的内在能力。相反，LSD1+8a与一种新的LSD1+8a相互作用蛋白 supervillin（SVIL）协同介导H3K9me2去甲基化。LSD1+8a的敲低会增加其靶启动子处的H3K9me2水平，但不会增加H3K4me2水平，并损害神经元分化。重要的是，SVIL与LSD1+8a结合的启动子共定位，其敲低模拟了LSD1+8a缺失的影响，支持SVIL作为神经元细胞中LSD1+8a的辅因子。这些发现为LSD1介导H3K9去甲基化的机制提供了见解，并突出了可变剪接作为LSD1获得选择性底物特异性（H3K9与H3K4）以差异控制神经元中特定基因表达程序的一种方式。
