Format

Send to

Choose Destination
Nat Commun. 2014 Dec 18;5:5815. doi: 10.1038/ncomms6815.

Epigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance.

Author information

1
1] State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100101, China.
2
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China.
3
1] State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China [2] Parkinson's Disease Center, Beijing Institute for Brain Disorders, Beijing 100101, China.

Abstract

Lysine-specific demethylase 1 (LSD1) is involved in gene regulation and development; however, its precise function, molecular targets and underlying mechanisms during development are poorly understood. Here we show that LSD1 is required for neuronal progenitor cell (NPC) maintenance during cortical development. A ChIP-seq analysis identified a LSD1-binding site (LBAL) downstream of Atrophin1 (ATN1). Surprisingly, tranylcypromine (LSD1 inhibitor) treatment increased H3K4 methylation at LBAL, leading to ATN1 repression and NPC differentiation. Knockdown of LSD1 and ATN1 phenocopied each other in inducing NPC premature differentiation and depletion, which could be rescued by ATN1 overexpression, suggesting that LSD1 controls NPC differentiation via regulation of ATN1 methylation status and expression. The involvement of LSD1 in ATN1 expression and NPC maintenance were confirmed in knockout mice. These findings hint at the potential application for the clinical drug, tranylcypromine, in the prevention and/or treatment of ATN1-associated degenerative disease, dentatorubral-pallidoluysian atrophy.

PMID:
25519973
PMCID:
PMC4284801
DOI:
10.1038/ncomms6815
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center