AF9 promotes hESC neural differentiation through recruiting TET2 to neurodevelopmental gene loci for methylcytosine hydroxylation.
AF9 promotes hESC neural differentiation through recruiting TET2 to neurodevelopmental gene loci for methylcytosine hydroxylation.
复制标题
AF9 通过将 TET2 招募到神经发育基因位点进行甲基胞嘧啶羟基化来促进 hESC 神经分化。
DOI：
10.1038/celldisc.2015.17
复制
发表时间：
2015
期刊：
影响因子：
33.5
通讯作者：
Jing N
中科院分区：
文献类型：
--
作者：
Qiao Y;Wang X;Wang R;Li Y;Yu F;Yang X;Song L;Xu G;Chin YE;Jing N
AF 9突变与人类神经发育疾病有关，并且鼠Af 9在皮质神经元生成期间介导组蛋白甲基化。然而，AF 9在人类神经发育中的功能和相关机制仍然未知。在这里，我们表明，AF 9是必要的和足够的人胚胎干细胞（hESC）的神经分化和神经发育基因激活。5-甲基胞嘧啶（5 mC）双加氧酶TET 2，这是确定在AF 9相关的蛋白质复合物，物理相互作用AF 9。AF 9和TET 2共定位于5-羟甲基胞嘧啶（5 hmC）阳性的hESC衍生的神经元，并需要适当的hESC神经分化。在与含有AAC的基序结合后，AF 9招募TET 2占据共同的神经发育基因位点，以指导5 mC到5 hmC的转换，随后依次激活神经靶基因和hESC神经定型。这些发现定义了用于调节人类神经发育的AF 9-TET 2调节复合物，并揭示了AF 9识别特异性和TET 2羟基化活性合作控制神经发育基因激活的新机制。
AF9 mutations have been implicated in human neurodevelopmental diseases and murine Af9 mediates histone methylation during cortical neuron generation. However, AF9 function and related mechanisms in human neurodevelopment remain unknown. Here we show that AF9 is necessary and sufficient for human embryonic stem cell (hESC) neural differentiation and neurodevelopmental gene activation. The 5-methylcytosine (5mC) dioxygenase TET2, which was identified in an AF9-associated protein complex, physically interacted with AF9. Both AF9 and TET2 co-localized in 5-hydroxymethylcytosine (5hmC)-positive hESC-derived neurons and were required for appropriate hESC neural differentiation. Upon binding to AAC-containing motifs, AF9 recruited TET2 to occupy the common neurodevelopmental gene loci to direct 5mC-to-5hmC conversion, which was followed by sequential activation of neural target genes and hESC neural commitment. These findings define an AF9–TET2 regulatory complex for modulating human neural development and reveal a novel mechanism by which the AF9 recognition specificity and TET2 hydroxylation activity cooperate to control neurodevelopmental gene activation.