Histone demethylase LSD1 regulates neural stem cell proliferation.
Lysine-specific demethylase 1 (LSD1) functions as a transcriptional coregulator by modulating histone methylation. Its role in neural stem cells has not been studied. We show here for the first time that LSD1 serves as a key regulator of neural stem cell proliferation. Inhibition of LSD1 activity or knockdown of LSD1 expression led to dramatically reduced neural stem cell proliferation. LSD1 is recruited by nuclear receptor TLX, an essential neural stem cell regulator, to the promoters of TLX target genes to repress the expression of these genes, which are known regulators of cell proliferation. The importance of LSD1 function in neural stem cells was further supported by the observation that intracranial viral transduction of the LSD1 small interfering RNA (siRNA) or intraperitoneal injection of the LSD1 inhibitors pargyline and tranylcypromine led to dramatically reduced neural progenitor proliferation in the hippocampal dentate gyri of wild-type adult mouse brains. However, knockout of TLX expression abolished the inhibitory effect of pargyline and tranylcypromine on neural progenitor proliferation, suggesting that TLX is critical for the LSD1 inhibitor effect. These findings revealed a novel role for LSD1 in neural stem cell proliferation and uncovered a mechanism for neural stem cell proliferation through recruitment of LSD1 to modulate TLX activity.
Sun
GuoQiang
G
Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Alzayady
Kamil
K
Stewart
Richard
R
Ye
Peng
P
Yang
Su
S
Li
Wendong
W
Shi
Yanhong
Y
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases; D006801:Humans; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010293:Pargyline / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014191:Tranylcypromine / Q000494:pharmacology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D008996:Monoamine Oxidase Inhibitors; C490258:Nr2e1 protein, mouse; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014191:Tranylcypromine; D010293:Pargyline; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D051059:PTEN Phosphohydrolase; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases