A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation

作者：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^*

来源：Molecular Cell, 2015, 57(6): 957-970.

DOI：10.1016/j.molcel.2015.01.010

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.

• 出版日期2015-3-19
• 单位复旦大学