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首页> 外文期刊>Cell discovery. >AF9 promotes hESC neural differentiation through recruiting TET2 to neurodevelopmental gene loci for methylcytosine hydroxylation
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AF9 promotes hESC neural differentiation through recruiting TET2 to neurodevelopmental gene loci for methylcytosine hydroxylation

机译：AF9通过将TET2募集到神经发育基因位点以促进甲基胞嘧啶羟基化来促进hESC神经分化

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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.
机译：AF9突变已牵涉到人类神经发育疾病，而鼠Af9在皮质神经元生成过程中介导组蛋白甲基化。然而，AF9功能和相关机制在人类神经发育中仍然未知。在这里，我们显示AF9对于人类胚胎干细胞（hESC）神经分化和神经发育基因激活是必要和充分的。在与AF9相关的蛋白质复合物中鉴定出的5-甲基胞嘧啶（5mC）双加氧酶TET2与AF9发生了物理相互作用。 AF9和TET2都共定位于5-羟甲基胞嘧啶（5hmC）阳性hESC衍生的神经元中，并且是适当hESC神经分化所必需的。结合包含AAC的基序后，AF9募集了TET2来占据常见的神经发育基因位点，以指导5mC到5hmC的转化，然后依次激活神经靶基因和hESC神经功能。这些发现定义了用于调节人类神经发育的AF9–TET2调控复合物，并揭示了一种新颖的机制，通过该机制，AF9识别特异性和TET2羟基化活性可以共同控制神经发育基因的激活。

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