Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner.
Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner.
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DOI：
10.1002/stem.1932
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发表时间：
2015-04
期刊：
影响因子：
5.2
通讯作者：
Lee, Sang-Hun
中科院分区：
文献类型：
--
作者：
He, Xi-Biao;Kim, Mirang;Kim, Seon-Young;Yi, Sang-Hoon;Rhee, Yong-Hee;Kim, Taeho;Lee, Eun-Hye;Park, Chang-Hwan;Dixit, Shilpy;Harrison, Fiona E.;Lee, Sang-Hun
细胞内维生素C（VC）在发育中的大脑中通过钠依赖性VC转运蛋白2（Svct 2）的活性维持在高水平，表明VC在大脑发育中的特定功能。最近有人提出VC作为Fe（II）-2-酮戊二酸依赖性双加氧酶的辅因子的作用。我们发现，VC补充胚胎中脑来源的神经干细胞（NSC）培养物大大增强了向中脑型DA（mDA）神经元，与帕金森病相关的神经元亚型的分化。VC诱导DA表型基因启动子中5-羟甲基胞嘧啶（5 hmC）的增加和H3 K27 m3的丢失，这两个作用分别由Tet 1和Jmjd 3催化。因此，VC通过Nurr 1增强了祖细胞中DA表型基因的转录，Nurr 1是mDA神经元发育的关键转录因子，更容易接近基因启动子。进一步的机制研究包括Tet 1和Jmjd 3敲低/抑制实验表明，5 hmC和H3 K27 m3的变化，特别是在祖细胞中，是VC介导的mDA神经元分化所必需的。我们最终发现，在Svct 2基因敲除小鼠胚胎中，发育中的中脑中的mDA神经元形成随着5 hmC/H3 k27 m3的变化而沿着减少。这些发现共同表明VC在中脑DA神经元发育中的表观遗传作用。
Intracellular Vitamin C (VC) is maintained at high levels in the developing brain by the activity of sodium-dependent VC transporter 2 (Svct2), suggesting specific VC functions in brain development. A role of VC as a cofactor for Fe(II)-2-oxoglutarate-dependent dioxygenases has recently been suggested. We show that VC supplementation in neural stem cell (NSC) cultures derived from embryonic midbrains greatly enhanced differentiation towards midbrain-type DA (mDA) neurons, the neuronal subtype associated with Parkinson’s disease. VC induced gain of 5-hydroxymethylcytosine (5hmC) and loss of H3K27m3 in DA phenotype gene promoters, which are catalyzed by Tet1 and Jmjd3, respectively. Consequently VC enhanced DA phenotype gene transcriptions in the progenitors by Nurr1, a transcription factor critical for mDA neuron development, to be more accessible to the gene promoters. Further mechanism studies including Tet1 and Jmjd3 knockdown/inhibition experiments revealed that both the 5hmC and H3K27m3 changes, specifically in the progenitor cells, are indispensible for the VC-mediated mDA neuron differentiation. We finally show that in Svct2 knockout mouse embryos, mDA neuron formation in the developing midbrain decreased along with the 5hmC/ H3k27m3 changes. These findings together indicate an epigenetic role of VC in midbrain DA neuron development.
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影响因子：
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