Li Di, Chen Yunhua, Zhu Xingyu, Yang Yanlei, Li Hongling, Zhao Robert Chunhua
Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Center for Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Beijing, China.
J Biomed Sci. 2025 Jan 8;32(1):6. doi: 10.1186/s12929-024-01098-3.
Obesity is becoming one of the major non-communicable diseases with increasing incidence and risks that cannot be ignored. However effective and safe clinical treatment strategies still need to be deeply explored. Increased number and volume of adipocytes lead to overweight and obesity. The aim of our work is to identify lncRNAs that have important regulatory in differentiation of human mesenchymal stem cells (MSCs) into adipocytes, and to provide effective targets for clinical prevention and treatment of obesity and related metabolic disorders.
We extracted primary MSCs from human adipose tissue, and conducted expression profile analysis of lncRNAs during adipogenic differentiation of MSCs to screen changed lncRNAs. Characteristics of lncRNA were revealed mainly by RACE and RNA FISH. Loss- and gain-of function experiments in vivo and in vitro were used to analyze effects of lncRNA. Targeted metabolomics was utilized to detect levels of free fatty acids. RNA pull-down, mRNA stability tests, etc. were employed to explore mechanisms of lncRNA.
Human-specific lncRNA, we named it MEK6-AS1, was the most up-regulated transcript during adipogenic differentiation of MSCs. MEK6-AS1 was highly expressed in adipose tissue samples from individuals with BMI ≥ 25 and positively correlated with adipogenic marker genes in these samples. Knocking down lncRNA inhibited expression of adipogenic differentiation markers and ectopic adipogenesis, reducing contents of various free fatty acids, as well as promoting osteogenic differentiation. Overexpression of lncRNA had the opposite effects to the above processes. We also found that MEK6-AS1 was elevated during hepatic steatosis organoid generation. Mechanistically, MEK6-AS1 worked partially through stabilization of MEK6 mRNA by NAT10.
We have identified a human-specific lncRNA (MEK6-AS1) with position information in the genomic database but has not been extensively reported. We demonstrated that MEK6-AS1 as a novel lncRNA involved in adipogenic differentiation and adipogenesis, fatty acid metabolism, and osteogenic differentiation. We found that MEK6-AS1 may exert its effect by enhancing MEK6 mRNA stability through NAT10. Our study may provide insights into implication of lncRNAs in stem cell biology and offer a new potential therapeutic target for the prevention and treatment of obesity and other related disease.
肥胖正成为主要的非传染性疾病之一，其发病率和风险不断增加，不容忽视。然而，有效且安全的临床治疗策略仍有待深入探索。脂肪细胞数量和体积的增加导致超重和肥胖。我们研究的目的是鉴定在人骨髓间充质干细胞（MSCs）向脂肪细胞分化过程中具有重要调节作用的长链非编码RNA（lncRNAs），并为肥胖及相关代谢紊乱的临床预防和治疗提供有效靶点。
我们从人脂肪组织中提取原代MSCs，并在MSCs成脂分化过程中进行lncRNAs的表达谱分析，以筛选出表达变化的lncRNAs。lncRNA的特征主要通过RACE和RNA FISH揭示。体内和体外的功能缺失和功能获得实验用于分析lncRNA的作用。靶向代谢组学用于检测游离脂肪酸水平。采用RNA下拉、mRNA稳定性测试等方法探索lncRNA的作用机制。
我们命名为MEK6-AS1的人特异性lncRNA是MSCs成脂分化过程中上调最明显的转录本。MEK6-AS1在BMI≥25的个体的脂肪组织样本中高表达，且与这些样本中的成脂标记基因呈正相关。敲低lncRNA可抑制成脂分化标记物的表达和异位脂肪生成，降低各种游离脂肪酸的含量，并促进成骨分化。lncRNA的过表达对上述过程具有相反的作用。我们还发现，在肝脂肪变性类器官生成过程中MEK6-AS1水平升高。机制上，MEK6-AS1部分通过NAT10使MEK6 mRNA稳定发挥作用。
我们鉴定出一种在基因组数据库中有位置信息但尚未被广泛报道的人特异性lncRNA（MEK6-AS1）。我们证明MEK6-AS1作为一种新型lncRNA参与成脂分化、脂肪生成、脂肪酸代谢和成骨分化。我们发现MEK6-AS1可能通过NAT10增强MEK6 mRNA稳定性发挥作用。我们的研究可能为lncRNAs在干细胞生物学中的作用提供见解，并为肥胖及其他相关疾病的预防和治疗提供新的潜在治疗靶点。
