GID complex regulates the differentiation of neural stem cells by destabilizing TET2

Abstract

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.

Keywords

TET2 / GID complex / neural stem cells / differentiation of neurons

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Acknowledgements

We thank Professor Caiyong Chen from College of Life Sciences, Zhejiang University for providing the FLAG-ARMC8 and FLAG-WDR26 plasmids. This study was supported by the National Science Foundation of China (Nos. 82071511 and 81120108011), National Key R&D Program of China (No. 2017YFE0103700), 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).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1007-9 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Meiling Xia, Rui Yan, Wenjuan Wang, Meng Zhang, Zhigang Miao, Bo Wan, and Xingshun Xu declare that they have no competing interests.

All animal use protocols were approved by the institutional animal care and use committee of Soochow University. All institutional and national guidelines for the care and use of laboratory animals were followed.

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