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

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,...

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Veröffentlicht in:Molecular cell 2015-03, Vol.57 (6), p.957-970
Hauptverfasser: 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
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container_end_page 970
container_issue 6
container_start_page 957
container_title Molecular cell
container_volume 57
creator 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
description 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. [Display omitted] •LSD1+8a isoform does not have the intrinsic property to demethylate H3K4•LSD1+8a functions as a co-activator by demethylating the repressive H3K9me2 mark•LSD1+8a interacts with SVIL; LSD1+8a/SVIL-containing complex demethylates H3K9me2•SVIL regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation Benoit Laurent et al. find that the neuro-enriched LSD1 isoform, LSD1+8a, mediates H3K9me2 demethylation in collaboration with the supervillin protein (SVIL), a new LSD1+8a partner. These findings highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to control specific transcriptional programs in neurons.
doi_str_mv 10.1016/j.molcel.2015.01.010
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[Display omitted] •LSD1+8a isoform does not have the intrinsic property to demethylate H3K4•LSD1+8a functions as a co-activator by demethylating the repressive H3K9me2 mark•LSD1+8a interacts with SVIL; LSD1+8a/SVIL-containing complex demethylates H3K9me2•SVIL regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation Benoit Laurent et al. find that the neuro-enriched LSD1 isoform, LSD1+8a, mediates H3K9me2 demethylation in collaboration with the supervillin protein (SVIL), a new LSD1+8a partner. 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subjects Alternative Splicing
Cell Differentiation
Cell Movement
Gene Expression Regulation
Gene Knockdown Techniques
HeLa Cells
Histone Demethylases - genetics
Histone Demethylases - metabolism
Histones - genetics
Histones - metabolism
Humans
Lysine - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Methylation
Microfilament Proteins - genetics
Microfilament Proteins - metabolism
Neurons - cytology
Neurons - metabolism
Promoter Regions, Genetic
Protein Isoforms - metabolism
title A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation
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