Sirtuin 1 Promotes Deacetylation of Oct4 and Maintenance of Naive Pluripotency

Abstract

The enhancer landscape is dramatically restructured as naïve 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 naïve state requires the NAD-dependent deacetylase, SirT1, which deacetylates Oct4. The activity of SirT1 is reduced during the naïve 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 provide strategies to manipulate epiblast cell state.

Methionine metabolism is essential for SIRT 1‐regulated mouse embryonic stem cell maintenance and embryonic development

“…In line with the increased survival rate, the surviving P1.5 SIRT1 KO pups under methionine supplemented diet had normal levels of H3K4me3 compared to WT and Het littermates (Fig G). Therefore, despite various mechanisms proposed for SIRT1's actions in mouse ESCs and embryogenesis (Han et al , ; Tang et al , ; Williams et al , ; Heo et al , ), our observations demonstrate that defective methionine metabolism is one of the major mechanisms that underlies SIRT1 deficiency‐induced compromise of pluripotency in mESCs and neonatal lethality in mice.…”

“…Whole‐body SIRT1 KO mice display severe developmental defects in multiple tissues on various mixed genetic backgrounds, including intrauterine growth retardation, developmental defects of the retina and heart, defective germ cell differentiation, and neonatal lethality (Cheng et al , ; McBurney et al , ; Wang et al , ). However, despite several reports about SIRT1 in differentiation and apoptosis of precursor/stem cells (Han et al , ; Prozorovski et al , ; Kang et al , ; Tang et al , ; Williams et al , ; Heo et al , ), the possible role of this key cellular metabolic sensor in metabolic regulation of ESC functions and embryonic development is completely unknown, and the molecular mechanisms underlying SIRT1 deficiency‐induced development defects remain elusive.…”

Adult neural stem cell fate is determined by thyroid hormone activation of mitochondrial metabolism

“…SIRT1 is known to be involved in regulating several metabolic pathways, especially mitochondrial function through PGC1α and AMPK [36] , [37] , [38] . SIRT1 also has an important role in stemness maintenance by directly regulating SOX2 [39] , OCT4 [40] and NANOG [41] , three major transcription factors required for pluripotency and inhibition of differentiation. As expected, our results show that SIRT1 is largely expressed in adult NSC-derived SOX2+ progenitors, but also preferentially maintained in early differentiation stages of the neuronal lineage.…”

Sirtuins in Metabolic and Epigenetic Regulation of Stem Cells

“…In hESCs, SIRT1 is under the transcriptional control of Oct4 and mediates Oct4-dependent pluripotency through repression of p53, a well-known SIRT1 deacetylation substrate [48]. In mESCs, SIRT1 is required for the maintenance of the naïve state through direct deacetylation of Oct4 [49]. During the naive-to-primed transition, the activity of SIRT1 is reduced and Oct4 becomes hyperacetylated.…”

“…During the naive-to-primed transition, the activity of SIRT1 is reduced and Oct4 becomes hyperacetylated. Acetylated Oct4 binds to an enhancer to induce the expression of Otx2, which in turn interacts with acetylated Oct4 to induce the primed pluripotency gene network [49].…”