The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
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DOI：
10.1038/ncb3147
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发表时间：
2015-05
影响因子：
21.3
通讯作者：
Mostoslavsky R
中科院分区：
文献类型：
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作者：
Etchegaray JP;Chavez L;Huang Y;Ross KN;Choi J;Martinez-Pastor B;Walsh RM;Sommer CA;Lienhard M;Gladden A;Kugel S;Silberman DM;Ramaswamy S;Mostoslavsky G;Hochedlinger K;Goren A;Rao A;Mostoslavsky R
胚胎干细胞（ESC）如何致力于特定的细胞谱系，并最终产生完全形成的生物体的所有细胞类型仍然是一个主要问题。ESC分化伴随着大规模的组蛋白和DNA修饰，但这两类表观遗传变化之间的关系尚不清楚。在这里，我们证明了组蛋白去乙酰化酶，sirtuin 6（Sirt 6），它的目标乙酰化组蛋白H3的赖氨酸9和56（H3 K9 ac和H3 K56 ac），和泰特（十-十一易位）酶，它将5-甲基胞嘧啶（5 mC）转化为5-羟甲基胞嘧啶（5 hmC）之间的层次相互作用。来源于Sirt 6敲除（S6 KO）小鼠的ESC偏向于神经外胚层发育。这种表型与Oct 4、Sox 2和Nanog的去阻遏相关，这反过来导致泰特酶的上调和5 hmC的产生升高。全基因组分析揭示了在S6 KO ESC中用5 hmC标记的神经外胚层基因的上调，从而暗示泰特酶在S6 KO ESC的神经外胚层偏斜分化表型中，其在Tets敲低后被完全拯救。我们证明了Sirt 6作为染色质调节剂的新作用，通过Tet-dependent调节5 hmC水平来维护多能性和分化之间的平衡。
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.