MicroRNA-29b/Tet1 regulatory axis epigenetically modulates mesendoderm differentiation in mouse embryonic stem cells.
MicroRNA-29b/Tet1 regulatory axis epigenetically modulates mesendoderm differentiation in mouse embryonic stem cells.
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DOI：
10.1093/nar/gkv653
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发表时间：
2015-09-18
影响因子：
14.9
通讯作者：
Lee TL
中科院分区：
文献类型：
--
作者：
Tu J;Ng SH;Luk AC;Liao J;Jiang X;Feng B;Lun Mak KK;Rennert OM;Chan WY;Lee TL
Tet家族介导的5-甲基胞嘧啶(5mC)DNA氧化为5-羟甲基胞嘧啶(5hmC)代表了一种新的表观遗传修饰，它调节胚胎干细胞(ESCs)分化过程中的动态基因表达。通过Tet对干细胞发育中5hmC调节的作用相对明确，Tet家族是如何调节的以及对ESCs谱系发育的影响仍然是未知的。在本研究中，我们发现Tet家族上的非编码RNA调节可能参与ESCs分化过程中的表观遗传调节，这是由Tet1 3‘非翻译区(3’UTR)上的microRNA-29b(miR-29b)结合位点所提示的。我们发现miR-29b在类胚体(EB)形成后急剧增加，导致ESCs分化过程中Tet1抑制和细胞5hmC水平下降。重要的是，我们发现这个miR-29b/Tet1调节轴在体外和体内都通过诱导Nodal信号通路和抑制活性去甲基化途径的关键靶点TDG来促进中内胚层谱系的形成。综上所述，我们的研究结果强调了小分子非编码RNA介导的调控对DNA去甲基化动力学的贡献，以及在ESCs谱系指定过程中关键的中胚层调节因子的差异表达。MIR-29b可能被用于丰富中胚层和内胚层衍生物的生产，并进一步分化为所需的器官特异性细胞。
Ten eleven translocation (Tet) family-mediated DNA oxidation on 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) represents a novel epigenetic modification that regulates dynamic gene expression during embryonic stem cells (ESCs) differentiation. Through the role of Tet on 5hmC regulation in stem cell development is relatively defined, how the Tet family is regulated and impacts on ESCs lineage development remains elusive. In this study, we show non-coding RNA regulation on Tet family may contribute to epigenetic regulation during ESCs differentiation, which is suggested by microRNA-29b (miR-29b) binding sites on the Tet1 3′ untranslated region (3′ UTR). We demonstrate miR-29b increases sharply after embyoid body (EB) formation, which causes Tet1 repression and reduction of cellular 5hmC level during ESCs differentiation. Importantly, we show this miR-29b/Tet1 regulatory axis promotes the mesendoderm lineage formation both in vitro and in vivo by inducing the Nodal signaling pathway and repressing the key target of the active demethylation pathway, Tdg. Taken together, our findings underscore the contribution of small non-coding RNA mediated regulation on DNA demethylation dynamics and the differential expressions of key mesendoderm regulators during ESCs lineage specification. MiR-29b could potentially be applied to enrich production of mesoderm and endoderm derivatives and be further differentiated into desired organ-specific cells.