@article{59842b49246c4114b383d40c5996970f,
title = "A SIRT1-LSD1 Corepressor Complex Regulates Notch Target Gene Expression and Development",
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.",
author = "Peter Mulligan and Fajun Yang and {Di Stefano}, Luisa and Ji, {Jun Yuan} and Jian Ouyang and Nishikawa, {Joy L.} and Debra Toiber and Madhura Kulkarni and Qun Wang and Najafi-Shoushtari, {S. Hani} and Raul Mostoslavsky and Gygi, {Steven P.} and Grace Gill and Dyson, {Nicholas J.} and N{\"a}{\"a}r, {Anders M.}",
note = "Funding Information: We thank Amy Walker for critical reading of the manuscript and Luhan Yang for valuable assistance and discussion. We express our gratitude to the groups of Vittorio Sartorelli and Mark Leid for sharing with us SIRT1 deletion constructs, Stephen Helfand and Kent Golic for dSir2 mutant flies, Spyros Artavanis-Tsakonas for Notch and Su(H) mutant flies, the Bloomington Drosophila Stock Center for various fly strains, Jon C. Aster for providing the pMigRI-ICN1 plasmid, John R. Whetstine for kind assistance in performing LSD1 demethylase assays, and members of the Massachusetts General Hospital (MGH) Cancer Center and Artavanis-Tsakonas' lab for helpful discussions. These studies were supported by National Institutes of Health grants R01GM071449 (A.M.N.), R01GM53203 (N.J.D.), R01GM077689 (G.G.), R01GM093072-01 (R.M.), and R01DK088190-01A1 (R.M.), the MGH-AstraZeneca Strategic Alliance (A.M.N.), the Sidney Kimmel Cancer Research Foundation (R.M.), a New Investigator Grant from the Massachusetts Life Sciences Center (R.M.), and an AFAR Research Grant (R.M.). P.M. was supported by a fellowship from the MGH Executive Committee on Research Fund for Medical Discovery, L.D.S. was supported by a Leukemia and Lymphoma Society fellowship, and D.T. was supported by the Brain Power for Israel Fund. ",
year = "2011",
month = jun,
day = "10",
doi = "10.1016/j.molcel.2011.04.020",
language = "English (US)",
volume = "42",
pages = "689--699",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}