Epigenetic dysregulation of Oxtr in Tet1-deficient mice has implications for neuropsychiatric disorders
Aaron J. Towers, … , Wei Xie, Yong-hui Jiang
Aaron J. Towers, … , Wei Xie, Yong-hui Jiang
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e120592. https://doi.org/10.1172/jci.insight.120592.
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Research Article Genetics Neuroscience

Epigenetic dysregulation of Oxtr in Tet1-deficient mice has implications for neuropsychiatric disorders

Abstract

OXTR modulates a variety of behaviors in mammals, including social memory and recognition. Genetic and epigenetic dysregulation of OXTR has been suggested to be implicated in neuropsychiatric disorders, including autism spectrum disorder (ASD). While the involvement of DNA methylation is suggested, the mechanism underlying epigenetic regulation of OXTR is largely unknown. This has hampered the experimental design and interpretation of the results of epigenetic studies of OXTR in neuropsychiatric disorders. From the generation and characterization of a new line of Tet1 mutant mice — by deleting the largest coding exon 4 (Tet1Δe4) — we discovered for the first time to our knowledge that Oxtr has an array of mRNA isoforms and a complex transcriptional regulation. Select isoforms of Oxtr are significantly reduced in the brain of Tet1Δe4–/– mice. Accordingly, CpG islands of Oxtr are hypermethylated during early development and persist into adulthood. Consistent with the reduced express of OXTR, Tet1Δe4–/– mice display impaired maternal care, social behavior, and synaptic responses to oxytocin stimulation. Our findings elucidate a mechanism mediated by TET1 protein in regulating Oxtr expression by preventing DNA hypermethylation of Oxtr. The discovery of epigenetic dysregulation of Oxtr in TET1-deficient mouse brain supports the necessity of a reassessment of existing findings and a value of future studies of OXTR in neuropsychiatric disorders.

Authors

Aaron J. Towers, Martine W. Tremblay, Leeyup Chung, Xin-lei Li, Alexandra L. Bey, Wenhao Zhang, Xinyu Cao, Xiaoming Wang, Ping Wang, Lara J. Duffney, Stephen K. Siecinski, Sonia Xu, Yuna Kim, Xiangyin Kong, Simon Gregory, Wei Xie, Yong-hui Jiang

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Figure 2

Tet1 deficiency results in significantly reduced expression of key neural genes, including Npas4 and Oxtr, in brain.

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Tet1 deficiency results in significantly reduced expression of key neur...
(A) A total of 186 genes were downregulated and 34 were upregulated in Tet1Δe4–/– hippocampus from RNA-seq analysis using FDR < 0.05 (n = 3/group). (B) Overall, the dysregulated genes in Tet1Δe4–/– hippocampus did not have a significant overlap with known neuronal activity–regulated genes reported in literate (533 genes). Dysregulated activity–dependent genes such as Npas4 were identified from this analysis. (C) Npas4 was downregulated in hippocampus from Tet1Δe4–/– mice (n = 6/group; *P = 0.017, 2-tailed t test). (D) Gene Ontology (cellular component classification) analysis using DAVID revealed an enrichment of extracellular dysregulated genes in Tet1Δe4–/– mice (Benjamini corrected P values indicated). (E) Oxtr was downregulated in hippocampus from Tet1Δe4–/– mice but not in Tet1Δe4–/– ESCs. Oxtr_ABEFG primers used. (**P < 0.005, 2-tailed t test; n = 5–6 for each genotype). (F) Significant overlap of ECS-treated Tet1Δe4–/– hippocampal dysregulated genes with dysregulated genes from neural progenitor cells (NPCs) of Tet1Δe11–13 (odds ratio [OR] = 7.66, P = 0.003) and untreated hippocampus of Tet1Δe5 mice (OR = 39.07, P = 2.3 × 10–57). All data are presented as mean ± SEM.