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PMID: 18391013 Published · ppublish English Journal Article

Transrepressive function of TLX requires the histone demethylase LSD1.

Molecular and cellular biology ·Vol. 28 ·No. 12 ·2008-06-00 ·Pages 3995-4003

Yokoyama A, Takezawa S, Schüle R, Kitagawa H, Kato S

Abstract

TLX is an orphan nuclear receptor (also called NR2E1) that regulates the expression of target genes by functioning as a constitutive transrepressor. The physiological significance of TLX in the cytodifferentiation of neural cells in the brain is known. However, the corepressors supporting the transrepressive function of TLX have yet to be identified. In this report, Y79 retinoblastoma cells were subjected to biochemical techniques to purify proteins that interact with TLX, and we identified LSD1 (also called KDM1), which appears to form a complex with CoREST and histone deacetylase 1. LSD1 interacted with TLX directly through its SWIRM and amine oxidase domains. LSD1 potentiated the transrepressive function of TLX through its histone demethylase activity as determined by a luciferase assay using a genomically integrated reporter gene. LSD1 and TLX were recruited to a TLX-binding site in the PTEN gene promoter, accompanied by the demethylation of H3K4me2 and deacetylation of H3. Knockdown of either TLX or LSD1 derepressed expression of the endogenous PTEN gene and inhibited cell proliferation of Y79 cells. Thus, the present study suggests that LSD1 is a prime corepressor for TLX.

MeSH Terms
Cell Line Cell Line, Tumor Cell Proliferation Gene Expression Regulation Genes, Reporter Histone Deacetylases/metabolism Histone Demethylases Histones/metabolism Humans Models, Biological Orphan Nuclear Receptors Oxidoreductases, N-Demethylating/metabolism,physiology Promoter Regions, Genetic Protein Structure, Tertiary Receptors, Cytoplasmic and Nuclear/metabolism
Chemicals
Histones NR2E1 protein, human Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear Histone Demethylases KDM1A protein, human Oxidoreductases, N-Demethylating Histone Deacetylases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yokoyama Atsushi
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Takezawa Shinichiro
Schüle Roland
Kitagawa Hirochika
Kato Shigeaki
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.02030-07
Published
2008-06-00
Epub
2008-00-07
Pages
3995-4003
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2423124
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.02030-07 PMC Full Text View journal details
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