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 6

Tet1Δe4–/– mice display impaired response to OXTR agonist stimulation but normal synaptic plasticity in the hippocampus.

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Tet1Δe4–/– mice display impaired response to OXTR agonist stimulation b...
(A) The frequency of spontaneous inhibitory current (sIPSC) at baseline and after TGOT stimulation in Tet1+/+ (n = 8 cells) and Tet1Δe4–/– (n = 10 cells) mice. The mean frequency at baseline for Tet1Δe4–/– (4.16 ± 0.67) was borderline lower than that of Tet1+/+ (2.47 ± 0.48) (P = 0.051, 2-tailed t test). Both Tet1e4+/+ and Tet1Δe4–/– cells showed the significant increased frequency in response to TGOT stimulation (Wilcoxon signed ranks test; P = 0.008 for +/+ and P = 0.01 for –/–). (B) The amplitude of spontaneous inhibitory current (sIPSC) at baseline and after TGOT stimulation in Tet1e4+/+ (n = 8 cells) and Tet1Δe4–/– (n = 10 cells) mice. The amplitude of sIPSC at baseline for Tet1Δe4–/– neurons (26.56 ± 6.78) was comparable with that of Tet1+/+ mice (20.36 ± 2.19). Tet1+/+ but not Tet1Δe4–/– cells showed the significant increased amplitude in response to TGOT stimulation (Wilcoxon signed ranks test; P = 0.006 for +/+ and P = 0.65 for –/–). (C) Baseline synaptic transmission not different in hippocampal CA1 of Tet1Δe4–/– mice. (n = 8 [–/–] slices from 5 mice; n = 11 [+/+] slices from 6 mice of 6–8 weeks old). (D) Paired pulse facilitation (PPF) not different in hippocampal CA1 of Tet1Δe4–/– mice indicating normal presynaptic function. (n = 8 [–/–] slices from 5 mice; n = 11 [+/+] slices from 6 mice of 6–8 weeks old). (E) Fiber volley not different in hippocampal CA1 of Tet1Δe4–/– mice indicating normal presynaptic function (n = 8 [–/–] slices from 5 mice; n = 11 [+/+] slices from 6 mice of 6–8 weeks old). (F) LTP in CA1 of Tet1Δe4–/– was not different from Tet1+/+ (+/+, 11 slices from 6 mice; LTP, 156% ± 6 %; –/–, 8 slice from 5 mice; LTP, 153% ± 12 %; 2-tailed t test). Arrow indicates the time of stimulation (HFS, 100 Hz, 1 second).