Long non-coding RNAs and small nucleolar RNA host gene 6 contribute to the depression-like behavior of hypothyroid mice by promoting methylation of the brain-derived neuropathic factor promoter that is mediated by DNA methyltransferase 1.

ABSTRACT

Long non-coding RNAs (lncRNAs) and small nucleolar RNA host gene 6 (SNHG6) have attracted extensive attention due to their involvement in various pathological processes. However, the functional role of lncRNA SNHG6 in depression-like behavior induced by hypothyroidism is still largely unknown. Our study was designed to explore the biological role of lncRNA SNHG6 in depression-like behavior induced by hypothyroidism and the underlying mechanisms. First, the depression-like behavior of hypothyroid mice was investigated after lncRNA SNHG6 knockdown. Subsequently, the regulation of the methylation levels of the brain-derived neurotrophic factor (BDNF) promoters by lncRNA SNHG6 was evaluated. To reveal the underlying mechanisms of lncRNA SNHG6 in the methylation of the BDNF promoters, RNA pull-down assays, RNA immunoprecipitation, and co-immunoprecipitation were performed. Further experiments were also conducted to investigate the roles of DNA (cytosine-5)-methyltransferase 1 (DNMT1) in the depression-like behavior induced by hypothyroidism. In this study, elevated levels of lncRNA SNHG6 were noted in the hippocampus in hypothyroid mice. Function assays proved that lncRNA SNHG6 knockdown alleviated the depression-like behavior induced by hypothyroidism. Furthermore, a mechanistic investigation validated that lncRNA SNHG6 stabilized DNMT1 by blocking UHRF1-mediated DNMT1 ubiquitination, which increased the methylation levels of the BDNF promoters. Moreover, DNMT1 was found to be involved in depression-like behavior in hypothyroid mice. Our findings revealed a novel mechanism by which lncRNA SNHG6 promotes the methylation levels of the BDNF promoters by stabilizing DNMT1 and sheds light on potential therapeutic strategies for depression-like behavior induced by hypothyroidism.