LincRNA通过编码蛋白小肽调节脂肪细胞代谢的分子机制研究

Previous studies have shown that lincRNAs play essential roles in regulating a variety of biological processes; however, recent findings indicate that the small open reading frames(sORF) presented in lincRNA sequences can be translated to functional peptides. We have previously characterized lincRNAs involved in adipose function, with which we discovered that LINC00116 can regulate adipocyte differentiation and maturation; moreover, we found that LINC00116 can also generate a small peptide with 56 amino acids, named PICO. To further study the working mechanisms of PICO and LINC00116 as well as their functional interactions, we propose to knock out PICO and LINC00116 in human pluripotent stem cells through genome editing tools, and also generate Pico knockout mice. Thus, though studies with a combination of hPSCs based cell platform and mouse models, we will look into the functions of PICO in regulating adipose metabolism and the whole body metabolic homeostasis. We will also compare the functions of PICO and LINC00116 to understand the possible functional interactions between the peptide (PICO) and the RNA (LINC00116) generated from the same genomic locus. Our studies will not only help to understand new regulators in adipose function, but will also reveal a possibly new working model of lincRNA genes.

长链非编码RNA作为一种新的基因形式参与多种细胞功能调控，其基因组序列中存在的微小开放阅读框（sORF）最近被发现可能编码蛋白小肽，行使生物学功能。我们前期针对参与脂肪组织代谢调控的lincRNA进行筛选研究，发现其中LINC00116参与调节脂肪细胞的分化和成熟；并且该“非编码”RNA同时编码长度为56个氨基酸的蛋白小肽，命名为PICO。为进一步研究PICO和LINC0016的功能及相互关联，我们拟通过基因组编辑技术分别构建PICO和LINC0016敲除人多能干细胞株及Pico敲除小鼠，综合多能干细胞平台和小鼠模型，从细胞、组织和机体多个层面，全面分析PICO小肽在脂肪代谢以及整体代谢平衡中的作用及其分子机制；同时针对PICO小肽和LINC00116之间是否存在功能或者调控机制的相互关联进行深入探讨。研究发现将同时对深入认识脂肪组织功能调节和lincRNA基因的分子作用机制有重要意义。

长链非编码RNA参与多种细胞功能调控，有意思的是，其基因组序列中存在的微小开放阅读框（sORF）被发现可编码蛋白小肽，行使特定生物学功能。我们前期发现LINC00116参与调节脂肪细胞的分化和成熟。进一步研究发现，LINC00116同时编码长度为56个氨基酸的蛋白小肽，命名为PICO。针对PICO的功能研究，我们通过基因组编辑技术分别构建了PICO敲除人多能干细胞株和Pico敲除小鼠，综合多能干细胞脂肪分化平台和小鼠模型，我们从细胞、组织和机体不同层面，分析了PICO小肽在脂肪代谢以及整体代谢平衡中的作用及其分子机制。研究发现PICO在脂肪细胞中是调控脂肪细胞线粒体功能的关键调控因子。PICO敲除的细胞线粒体能量代谢受损，导致脂质过度积累；同时KO小鼠呈现明显的肥胖和胰岛素抵抗等代谢慢病相关表型。进一步深入研究发现，PICO定位在线粒体，和线粒体氧化呼吸链蛋白有蛋白相互作用，继而影响了线粒体能量代谢。综上，我们鉴定出一个LINCRNA编码的小肽可以直接调控线粒体功能，继而影响代谢平衡，为进一步理解LINCRNA功能提供了重要基础。