The ten-eleven translocation (Tet) family of dioxygenases convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Previous studies have shown that 5hmC-mediated epigenetic modifications play essential roles in diverse biological processes and diseases. Here we show that Tet proteins and 5hmC display dynamic features during postnatal cardiac development and that Tet2 is the predominant dioxygenase present in heart. Tet2 knockout (KO) results in abnormal cardiac function, progressive cardiac hypertrophy and fibrosis. Mechanistically, Tet2 deficiency leads to reduced hydroxymethylation in the cardiac genome and alters the cardiac transcriptome. Mechanistically, Tet2 loss leads to a decrease of Hspa1b expression, a regulator of the Erk signaling pathway, which leads to over-activation of Erk signaling. Acute Hspa1b knock down increased the phosphorylation of Erk and induced hypertrophy of cardiomyocytes, which could be blocked by Erk signaling inhibitor. Consistently, ectopic expression of Hspal1b was able to rescue the deficits of cardiomyocytes induced by Tet2 depletion. Taken together, our study’s results reveal the important roles of Tet2-mediated DNA hydroxymethylation in cardiac development and function.
Previous studies have shown the essential roles of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in neuronal development, function and neurological diseases. However, the function of Ogt and O-GlcNAcylation in the adult cerebellum has not been well elucidated. Here, we have found that cerebellum has the highest level of O-GlcNAcylation relative to cortex and hippocampus of adult male mice. Specific deletion ofOgtin granule neuronal precursors (GNPs) induces abnormal morphology and decreased size of the cerebellum in adult maleOgtdeficient (cKO) mice. Adult male cKO mice show the reduced density and aberrant distribution of cerebellar granule cells (CGCs), the disrupted arrangement of Bergman glia and Purkinje cells. In addition, adult male cKO mice exhibit aberrant synaptic connection, impaired motor coordination, and learning and memory abilities. Mechanistically, we have identified G protein subunit alpha 12 (Gα12) is modified by Ogt-mediated O-GlcNAcylation. O-GlcNAcylation of Gα12 facilitates its binding to Rho guanine nucleotide exchange factor 12 (Arhgef12) and consequently activates RhoA/ROCK signaling. RhoA/ROCK pathway activator LPA can rescue the developmental deficits ofOgtdeficient CGCs. Therefore, our study has revealed the critical function and related mechanisms of Ogt and O-GlcNAcylation in the cerebellum of adult male mice.SIGNIFICANCE STATEMENT:Cerebellar function are regulated by diverse mechanisms. To unveil novel mechanisms is critical for understanding the cerebellar function and the clinical therapy of cerebellum-related diseases. In the present study, we have shown that O-GlcNAc transferase gene (Ogt) deletion induces abnormal cerebellar morphology, synaptic connection, and behavioral deficits of adult male mice. Mechanistically, Ogt catalyzes O-GlcNAcylation of Gα12, which promotes the binding to Arhgef12, and regulates RhoA/ROCK signaling pathway. Our study has uncovered the important roles of Ogt and O-GlcNAcylation in regulating cerebellar function and cerebellum-related behavior. Our results suggest that Ogt and O-GlcNAcylation could be potential targets for some cerebellum-related diseases.
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