Sirtuin 1 regulation of developmental genes during differentiation of stem cells.
The longevity-promoting NAD+-dependent class III histone deacetylase Sirtuin 1 (SIRT1) is involved in stem cell function by controlling cell fate decision and/or by regulating the p53-dependent expression of NANOG. We show that SIRT1 is down-regulated precisely during human embryonic stem cell differentiation at both mRNA and protein levels and that the decrease in Sirt1 mRNA is mediated by a molecular pathway that involves the RNA-binding protein HuR and the arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1). SIRT1 down-regulation leads to reactivation of key developmental genes such as the neuroretinal morphogenesis effectors DLL4, TBX3, and PAX6, which are epigenetically repressed by this histone deacetylase in pluripotent human embryonic stem cells. Our results indicate that SIRT1 is regulated during stem cell differentiation in the context of a yet-unknown epigenetic pathway that controls specific developmental genes in embryonic stem cells.
Calvanese
Vincenzo
V
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, 28049 Madrid, Spain.
Lara
Ester
E
Suárez-Alvarez
Beatriz
B
Abu Dawud
Raed
R
Vázquez-Chantada
Mercedes
M
Martínez-Chantar
Maria Luz
ML
Embade
Nieves
N
López-Nieva
Pilar
P
Horrillo
Angelica
A
Hmadcha
Abdelkrim
A
Soria
Bernat
B
Piazzolla
Daniela
D
Herranz
Daniel
D
Serrano
Manuel
M
Mato
Jose María
JM
Andrews
Peter W
PW
López-Larrea
Carlos
C
Esteller
Manel
M
Fraga
Mario F
MF
D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D020871:RNA Stability; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D053468:CARD Signaling Adaptor Proteins; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C426242:CARD11 protein, human; D006162:Guanylate Cyclase