Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin.
We characterized human SirT1, one of the human homologs of the budding yeast Sir2p, an NAD+-dependent histone deacetylase involved in establishing repressive chromatin and increased life span. SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro. RNAi-mediated decreased expression of SirT1 in human cells causes hyperacetylation of H4-K16 and H3-K9 in vivo. SirT1 interacts with and deacetylates histone H1 at lysine 26. Using an inducible system directing expression of SirT1 fused to the Gal4-DNA binding domain and a Gal4-reporter integrated in euchromatin, Gal4-SirT1 expression resulted in the deacetylation of H4-K16 and H3-K9, recruitment of H1 within the promoter vicinity, drastically reduced reporter expression, and loss of H3-K79 methylation, a mark restricting silenced chromatin. We propose a model for SirT1-mediated heterochromatin formation that includes deacetylation of histone tails, recruitment and deacetylation of histone H1, and spreading of hypomethylated H3-K79 with resultant silencing.
Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Alejandro
A
Vaquero
Michael
M
Scher
Donghoon
D
Lee
Hediye
H
Erdjument-Bromage
Paul
P
Tempst
Danny
D
Reinberg
D000107:Acetylation; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006570:Heterochromatin / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009243:NAD / Q000378:metabolism; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*
D006570:Heterochromatin; D006657:Histones; D009243:NAD; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases