The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine

Abstract

How embryonic stem cells (ESC) commit to specific cell lineages and ultimately yield all cell types of a fully formed organism remains a major question. ESC differentiation is accompanied by large-scale histone and DNA modifications, but the relations between these two categories of epigenetic changes are not understood. Here we demonstrate the hierarchical interplay between the histone deacetylase, sirtuin 6 (Sirt6), which targets acetylated histone H3 at lysines 9 and 56 (H3K9ac and H3K56ac), and the Tet (Ten-eleven translocation) enzymes, which convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). ESCs derived from Sirt6 knockout (S6KO) mice are skewed towards neuroectoderm development. This phenotype is associated with derepression of Oct4, Sox2 and Nanog, which in turn causes an upregulation of Tet enzymes and elevated production of 5hmC. Genome-wide analysis revealed an upregulation of neuroectoderm genes marked with 5hmC in S6KO ESCs, thereby implicating Tet enzymes in the neuroectoderm-skewed differentiation phenotype of S6KO ESCs, which is fully rescued upon knockdown of Tets. We demonstrate a new role for Sirt6 as a chromatin regulator safeguarding the balance between pluripotency and differentiation through Tet-dependent regulation of 5hmC levels.

LncPRESS1 Is a p53-Regulated LncRNA that Safeguards Pluripotency by Disrupting SIRT6-Mediated De-acetylation of Histone H3K56

“…Among these, SIRT6 enrichment in lncPRESS1 pull-downs yielded considerably higher number of peptides and better interaction scores in two replicates (Supplemental Table S5). SIRT6 was recently shown to control ESC fate by regulating the levels of H3K56ac (Etchegaray et al, 2015), previously linked to the pluripotency-associated transcriptional network in hESCs (Xie et al, 2009). Therefore, we prioritized understanding functions of lncPRESS1 -SIRT6 interactions.…”

“…High levels of H3K56ac correlate with transcriptional activation of pluripotency-specific genes and are diminished significantly during ESC differentiation (Tan et al, 2013; Xie et al, 2009). Deacetylation of H3K9ac and H3K56ac is mediated by SIRT6 to repress expression of OCT4 , SOX2 and NANOG and promote hESC differentiation (Etchegaray et al, 2015). SIRT6 is a chromatin-bound (Kugel and Mostoslavsky, 2014; McCord et al, 2009), NAD-dependent deacetylase of H3K9ac (Michishita et al, 2008) and H3K56ac (Michishita et al, 2009; Yang et al, 2009).…”

DNA Methylation Dynamics in Neurogenesis

“…The depletion of SIRT6 caused a derepression of Oct4 and Sox2, which triggers upregulation of Tet1 and Tet2 and a gain of 5hmC in neuroectoderm genes, including the Hoxa gene cluster, which is implicated in neural crest development, and Gata2 and Pax6, which are implicated in neurogenesis. Hyperhydromethylation leads to overexpression of neuroectoderm proteins, which results in skewed development toward neuroectoderm [81].…”

As“SIRT”ing the role of an epigenetic modifier in hematopoietic stem cell homeostasis

“…SIRT6 also regulates ESC homeostasis by repressing pluripotent genes Oct4, Nanog and Sox2 through deacetylation of H3K56. Loss of SIRT6 reduces ESC proliferation (16), derepresses the pluripotent genes, increases TET expression and subsequent 5-hydroxymethylcytosine leading to skewed differentiation of ESCs towards neural ectoderm (17). SIRT6 is involved in base excision repair and suppresses genomic instability and acts as an anti-ageing factor.…”