Loss of TET Activity in the Postnatal Mouse Brain Perturbs Synaptic Gene Expression and Impairs Cognitive Function
Ji‑Wei Liu1 · Ze‑Qiang Zhang2 · Zhi‑Chuan Zhu3 · Kui Li3,4 · Qiwu Xu3,4 · Jing Zhang3 · Xue‑Wen Cheng3 · Han Li5 · Ying Sun1 · Ji‑Jun Wang5 · Lu‑Lu Hu6 · Zhi‑Qi Xiong2,3,7 · Yongchuan Zhu51 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 20031, China
4 Lingang Laboratory, Shanghai 201602, China
5 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
6 Fudan University Institutes of Biomedical Sciences, Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Shanghai Medical College of Fudan University, Shanghai 200032, China
7 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201602, China
Abstract
Conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family proteins leads to the accumulation of 5hmC in the central nervous system; however, the role of 5hmC in the postnatal brain and how its levels and target genes are regulated by TETs remain elusive. We have generated mice that lack all three Tet genes specifically in postnatal excitatory neurons. These mice exhibit significantly reduced 5hmC levels, altered dendritic spine morphology within brain regions crucial for cognition, and substantially impaired spatial and associative memories. Transcriptome profiling combined with epigenetic mapping reveals that a subset of genes, which display changes in both 5hmC/5mC levels and expression patterns, are involved in synapse-related functions. Our findings provide insight into the role of postnatally accumulated 5hmC in the mouse brain and underscore the impact of 5hmC modification on the expression of genes essential for synapse development and function.
Keywords
5hmC; TET; DNA demethylation; Synapse; Learning and memory; Epigenetics
