Brain development requires a delicate balance between self-renewal and differentiation in neural stem cells(NSC),which rely on the precise regulation of gene expression.Ten-eleven translocation 2(TET2)modulates gene e...Brain development requires a delicate balance between self-renewal and differentiation in neural stem cells(NSC),which rely on the precise regulation of gene expression.Ten-eleven translocation 2(TET2)modulates gene expression by the hydroxymethylation of 5-methylcytosine in DNA as an important epigenetic factor and participates in the neuronal differentiation.Yet,the regulation of TET2 in the process of neuronal differentiation remains unknown.Here,the protein level of TET2 was reduced by the ubiquitin-proteasome pathway during NSC differentiation,in contrast to mRNA level.We identified that TET2 physically interacts with the core subunits of the glucose-induced degradation-deficient(GID)ubiquitin ligase complex,an evolutionarily conserved ubiquitin ligase complex and is ubiquitinated by itself.The protein levels of GID complex subunits increased reciprocally with TET2 level upon NSC differentiation.The silencing of the core subunits of the GID complex,including WDR26 and ARMC8,attenuated the ubiquitination and degradation of TET2,increased the global 5-hydroxymethylcytosine levels,and promoted the differentiation of the NSC.TET2 level increased in the brain of the Wdr26^(+/-)mice.Our results illustrated that the GID complex negatively regulates TET2 protein stability,further modulates NSC differentiation,and represents a novel regulatory mechanism involved in brain development.展开更多
基金supported by the National Science Foundation of China(Nos.82071511 and 81120108011)National Key R&D Program of China(No.2017YFE0103700)+1 种基金Shandong Provincial Natural Science Foundation(No.ZR2019ZD32)the Priority Academic Program Development of Jiangsu Higher Education Institutions,and Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX21_2974).
文摘Brain development requires a delicate balance between self-renewal and differentiation in neural stem cells(NSC),which rely on the precise regulation of gene expression.Ten-eleven translocation 2(TET2)modulates gene expression by the hydroxymethylation of 5-methylcytosine in DNA as an important epigenetic factor and participates in the neuronal differentiation.Yet,the regulation of TET2 in the process of neuronal differentiation remains unknown.Here,the protein level of TET2 was reduced by the ubiquitin-proteasome pathway during NSC differentiation,in contrast to mRNA level.We identified that TET2 physically interacts with the core subunits of the glucose-induced degradation-deficient(GID)ubiquitin ligase complex,an evolutionarily conserved ubiquitin ligase complex and is ubiquitinated by itself.The protein levels of GID complex subunits increased reciprocally with TET2 level upon NSC differentiation.The silencing of the core subunits of the GID complex,including WDR26 and ARMC8,attenuated the ubiquitination and degradation of TET2,increased the global 5-hydroxymethylcytosine levels,and promoted the differentiation of the NSC.TET2 level increased in the brain of the Wdr26^(+/-)mice.Our results illustrated that the GID complex negatively regulates TET2 protein stability,further modulates NSC differentiation,and represents a novel regulatory mechanism involved in brain development.
