title: Sirtuin 1 Promotes Deacetylation of Oct4 and Maintenance of Naive Pluripotency.
abstract: The enhancer landscape is dramatically restructured as naive preimplantation epiblasts transition to the post-implantation state of primed pluripotency. A key factor in this process is Otx2, which is upregulated during the early stages of this transition and ultimately recruits Oct4 to a different set of enhancers. In this study, we discover that the acetylation status of Oct4 regulates the induction of the primed pluripotency gene network. Maintenance of the naive state requires the NAD-dependent deacetylase, SirT1, which deacetylates Oct4. The activity of SirT1 is reduced during the naive-to-primed transition; Oct4 becomes hyper-acetylated and binds to an Otx2 enhancer to induce Otx2 expression. Induction of Otx2 causes the reorganization of acetylated Oct4 and results in the induction of the primed pluripotency gene network. Regulation of Oct4 by SirT1 may link stem cell development to environmental conditions, and it may provide strategies to manipulate epiblast cell state.
authors.affiliation: Glenn Laboratory for the Science of Aging and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Williams
authors.affiliation: Glenn Laboratory for the Science of Aging and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Taylor
authors.affiliation: Glenn Laboratory for the Science of Aging and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.affiliation: Glenn Laboratory for the Science of Aging and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Lim
authors.affiliation: Glenn Laboratory for the Science of Aging and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kim
authors.affiliation: Glenn Laboratory for the Science of Aging and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: leng@mit.edu.
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
mesh_terms: D000107:Acetylation; D000818:Animals; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D005855:Germ Layers / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D051857:Otx Transcription Factors / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050814:Octamer Transcription Factor-3; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C494174:Pou5f1 protein, mouse; D012333:RNA, Messenger; D056564:Sirtuin 1
keywords: EpiLC; NAD; Oct4; SirT1; Sirtuin; aging; enhancer; naïve pluripotency; primed pluripotency; stem cells