RRC ID 36050
Author Hirano K, Namihira M.
Title LSD1 Mediates Neuronal Differentiation of Human Fetal Neural Stem Cells by Controlling the Expression of a Novel Target Gene, HEYL.
Journal Stem Cells
Abstract Histone-modifying enzymes dynamically regulate the chromatin status and have been implicated in the fate specification of stem cells, including neural stem cells (NSCs), which differentiate into three major cell types: neurons, astrocytes, and oligodendrocytes. Lysine-specific demethylase 1 (LSD1, also known as KDM1A) catalyzes the demethylation of H3K4me1/2 and H3K9me1/2, and it was recently suggested that functional disruption of LSD1 links to various human diseases. However, the mechanism by which LSD1 regulates human neural development remains unclear. Here, we present evidence that specific inhibition of LSD1 suppresses the neurogenesis of cultured human fetal NSCs (hfNSCs) isolated from the human fetal neocortex. Notably, we found that LSD1 directly associates with the promoter of the HEYL gene, and controls the demethylation of H3K4me2, which is accompanied by repression of HEYL expression during hfNSC neuronal differentiation. Furthermore, we also showed that HEYL expression is sufficient to inhibit the neuronal differentiation of hfNSCs. This mechanism seems to be primate-specific because mouse NSCs do not exhibit the LSD1 inhibitor-induced upregulation of Heyl. Our findings suggest that LSD1 plays an important role in primate neurogenesis and may contribute to the characterization of an evolved primate brain. Stem Cells 2016;34:1872-1882.
Volume 34(7)
Pages 1872-82
Published 2016-7-1
DOI 10.1002/stem.2362
PMID 27018646
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / genetics* Basic Helix-Loop-Helix Transcription Factors / metabolism Cell Differentiation* / genetics Cell Proliferation Chromatin / metabolism Fetus / cytology* Gene Expression Regulation* Histone Demethylases / metabolism* Histones / metabolism Humans Lysine / metabolism Methylation Mice, Inbred ICR Neocortex / cytology Neural Stem Cells / cytology* Neural Stem Cells / metabolism Neurogenesis / genetics Neurons / cytology* Neurons / metabolism Promoter Regions, Genetic / genetics Repressor Proteins / genetics* Repressor Proteins / metabolism
IF 6.022
Times Cited 17
DNA material Genome Network Project cDNA Clone IRAL018B15 (HGY087239) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393).