title: AF9 promotes hESC neural differentiation through recruiting TET2 to neurodevelopmental gene loci for methylcytosine hydroxylation.
abstract: 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.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine , Shanghai, China.
authors.forename: Xiongjun
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
authors.forename: Xianfa
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Song
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine , Shanghai, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Naihe
authors.initials: N
authors.lastname: Jing
keywords: 5-hydroxymethylcytosine; AF9; TET2; human embryonic stem cell; neural differentiation