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PMID: 21596603 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development.

Molecular cell ·Vol. 42 ·No. 5 ·2011-06-10 ·Pages 689-99

Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, Toiber D, Kulkarni M, Wang Q, Najafi-Shoushtari SH, Mostoslavsky R, Gygi SP, Gill G, Dyson NJ, Näär AM

Abstract

Epigenetic regulation of gene expression by histone-modifying corepressor complexes is central to normal animal development. The NAD(+)-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear. We describe here a SIRT1 corepressor complex containing the histone H3K4 demethylase LSD1/KDM1A and several other LSD1-associated proteins. SIRT1 and LSD1 interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway. Mutations in Drosophila SIRT1 and LSD1 orthologs result in similar developmental phenotypes and genetically interact with the Notch pathway in Drosophila. These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans.

MeSH Terms
Animals Drosophila Proteins/genetics,metabolism,physiology Drosophila melanogaster/genetics,growth & development Epigenesis, Genetic Gene Expression Regulation, Developmental Histones/metabolism Immunoprecipitation Mutation Oxidoreductases, N-Demethylating/genetics,metabolism,physiology Phenotype Receptors, Notch/genetics,metabolism Sirtuin 1/genetics,metabolism,physiology
Chemicals
Drosophila Proteins Histones N protein, Drosophila Receptors, Notch Lsd-1 protein, Drosophila Oxidoreductases, N-Demethylating Sirtuin 1
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Mulligan Peter
Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.
Yang Fajun
Di Stefano Luisa
Ji Jun-Yuan
Ouyang Jian
Nishikawa Joy L
Toiber Debra
Kulkarni Madhura
Wang Qun
Najafi-Shoushtari S Hani
Mostoslavsky Raul
Gygi Steven P
Gill Grace
Dyson Nicholas J
Näär Anders M
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2011.04.020
Published
2011-06-10
Epub
2011-00-19
Pages
689-99
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3119599
Subset
IM
Grants
NIDDK NIH HHS · R01 DK093623 · United States
NIGMS NIH HHS · R01 GM071449 · United States
NIGMS NIH HHS · R01 GM053203 · United States
NIGMS NIH HHS · R01GM53203 · United States
NIGMS NIH HHS · R01 GM071449-01A1 · United States
NIGMS NIH HHS · R01GM077689 · United States
NIDDK NIH HHS · R01DK088190-01A1 · United States
NIGMS NIH HHS · R01 GM071449-05S1 · United States
NIGMS NIH HHS · R01 GM093072 · United States
NIGMS NIH HHS · R01GM093072-01 · United States
NIGMS NIH HHS · R01GM071449 · United States
NIGMS NIH HHS · R01 GM077689 · United States
NIDDK NIH HHS · R01 DK088190 · United States
Corrections
CommentIn
PMID: 21658598
External Links
PubMed source DOI: 10.1016/j.molcel.2011.04.020 PMC Full Text View journal details
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