Long non-coding RNA LncCplx2 regulates glucose homeostasis and pancreatic β cell function

作者：Linlin Wang, Liqiao Hu, Xingyue Wang, Zhaoxu Geng, Meng Wan, Junfeng Hao, Huisheng Liu, Yuying Fan, Tao Xu, Zonghong Li · 发表于：Molecular Metabolism · 年份：2024 · DOI：10.1016/j.molmet.2024.101878 · 被引用次数：6 · 研究领域：Circadian rhythm and melatonin、Cancer-related molecular mechanisms research、Dietary Effects on Health

OBJECTIVE: Numerous studies have highlighted the role of clock genes in diabetes disease and pancreatic β cell functions. However, whether rhythmic long non-coding RNAs involve in this process is unknown. METHODS: RNA-seq and 3' rapid amplification of cDNA ends (RACE)-PCR were used to identify the rat LncCplx2 in pancreatic β cells. The subcellular analysis with qRT-PCR and RNA-Scope were used to assess the localization of LncCplx2. The effects of LncCplx2 overexpression or knockout (KO) on the regulation of pancreatic β cell functions were assessed in vitro and in vivo. RNA-seq, immunoblotting (IB), Immunoprecipitation (IP), RNA pull-down, and chromatin immunoprecipitation (ChIP)-PCR assays were employed to explore the regulatory mechanisms through LncRNA-protein interaction. Metabolism cage was used to measure the circadian behaviors. RESULTS: We first demonstrate that LncCplx2 is a conserved nuclear long non-coding RNA and enriched in pancreatic islets, which is driven by core clock transcription factor BMAL1. LncCplx2 is downregulated in the diabetic islets and repressed by high glucose, which regulates the insulin secretion in vitro and ex vivo. Furthermore, LncCplx2 KO mice exhibit diabetic phenotypes, such as high blood glucose and impaired glucose tolerance. Notably, LncCplx2 deficiency has significant effects on circadian behavior, including prolonged period duration, decreased locomotor activity, and reduced metabolic rates. Mechanistically, LncCplx2 recruits EZH2, ...