Tet1 Regulates Astrocyte Development and Cognition of Mice Through Modulating GluA1

Weize Xu; Xicheng Zhang; Feng Liang; Yuhang Cao; Ziyi Li; Wenzheng Qu; Jinyu Zhang; Yanhua Bi; Chongran Sun; Jianmin Zhang; Binggui Sun; Qiang Shu; Xuekun Li

doi:10.3389/fcell.2021.644375

Tet1 Regulates Astrocyte Development and Cognition of Mice Through Modulating GluA1

Front Cell Dev Biol. 2021 Oct 28:9:644375. doi: 10.3389/fcell.2021.644375. eCollection 2021.

Authors

Weize Xu^{1

2}, Xicheng Zhang^{1

2}, Feng Liang³, Yuhang Cao^{1

2

4}, Ziyi Li⁵, Wenzheng Qu^{1

2}, Jinyu Zhang^{1

2

4}, Yanhua Bi¹, Chongran Sun³, Jianmin Zhang³, Binggui Sun⁶, Qiang Shu^{1

2}, Xuekun Li^{1

2

4}

Affiliations

¹ The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² National Clinical Research Center for Child Health, Hangzhou, China.
³ The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁴ The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
⁶ Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Tet (Ten eleven translocation) family proteins-mediated 5-hydroxymethylcytosine (5hmC) is highly enriched in the neuronal system, and is involved in diverse biological processes and diseases. However, the function of 5hmC in astrocyte remains completely unknown. In the present study, we show that Tet1 deficiency alters astrocyte morphology and impairs neuronal function. Specific deletion of Tet1 in astrocyte impairs learning and memory ability of mice. Using 5hmC high-throughput DNA sequencing and RNA sequencing, we present the distribution of 5hmC among genomic features in astrocyte and show that Tet1 deficiency induces differentially hydroxymethylated regions (DhMRs) and alters gene expression. Mechanistically, we found that Tet1 deficiency leads to the abnormal Ca²⁺ signaling by regulating the expression of GluA1, which can be rescued by ectopic GluA1. Collectively, our findings suggest that Tet1 plays important function in astrocyte physiology by regulating Ca²⁺ signaling.

Keywords: GluA1; Tet1; astrocyte; cognition; neuronal development.