The human central nervous system (CNS) is immensely complex with composition of precisely interconnected neurons, which is generated relying on the early neurodevelopment processes controlled by signaling pathways, intrinsic factors, and epigenetic regulations. However, the epigenetic mechanisms underlying human neural gene activation and lineage commitment remain largely elusive. 

Dr. JING Naihe's group at Institute of Biochemistry and Cell Biology, and Dr. CHIN Y Eugene's group at Institute of Health Sciences, Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences, reported the functions of an epigenetic modifier-AF9 in human embryonic stem cell (hESC) neural differentiation through mediating DNA methylation by interaction with TET2. AF9 mutations have been implicated in human neurodevelopmental diseases, while its specific function in human neurodevelopment remain unknown. Here researchers show that AF9 is necessary and sufficient for hESC neural differentiation and neurodevelopmental gene activation. 

To investigate the mechanism of AF9 in hESC neural commitment, researchers identified the components of AF9-associated protein complex, and the 5-methylcytosine (5mC) dioxygenase TET2 was identified to physically interact with AF9. Interestingly, TET2 was also required for appropriate hESC neural differentiation. ChIP-seq analysis revealed that AF9 and TET2 were enriched in the common neurodevelopmental gene loci to direct 5mC-to-5hmC conversions and subsequent neural gene activation. More importantly, the TET2 binding activity on these neural gene loci was dependent on the prior enrichment of AF9 in AAC-containing motifs.  

These findings define an AF9-TET2 regulatory complex for modulating human neurodevelopment and uncover a novel mechanism by which the AF9 recognition specificity and TET2 hydroxylation activity cooperate to control neurodevelopmental gene activation.  

The study provides a solution for the targeting specificity of TET proteins to specifically catalyze DNA hydroxylation, possibly by interaction with specific co-factors.  

This study entitled “AF9 Promotes hESC Neural Differentiation through Recruiting TET2 to Neurodevelopmental Gene Loci for Methylcytosine Hydroxylation” was published online in Cell Discovery on July 28, 2015. 

This work was funded by grants from the Chinese Academy of Sciences, the Ministry of Science and Technology of China, and the National Natural Science Foundation of China. 

Fig. A model for the role of the AF9-TET2 complex in the modulation of hESC neural differentiation.
In hESCs, some neural gene loci are methylated and inactive. During neural differentiation, upregulated AF9 are enriched in the neurodevelopmental gene loci by recognizing the AAC-containing elements. Then, AF9 recruits TET2 to nearby C-rich DNA sequences through the TET2 catalytic domain, and the AF9-TET2 complex cooperates to direct the 5mC conversion to 5hmC or to unmethylated cytosine (C). The AF9-TET2 complex-mediated 5mC-to-5hmC conversions results in the activation of multiple neural genes and hESC differentiation into neurons. (Image by Prof. JING Naihe`s group)

CONTACT:
JING Naihe
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, China
Tel.: +86-21-5492-1381;
E-mail: njing@sibcb.ac.cn