The repression of the lipolytic inhibitor G0s2 enhancers affects lipid metabolism.

IF 2.6 3区 生物学 Q2 GENETICS & HEREDITY
Gene Pub Date : 2024-12-10 DOI:10.1016/j.gene.2024.149162
Ziqi Li, Sha Zeng, Qinjiao Du, Xiaokai Li, Qiuyue Chen, Songling Zhang, Xun Zhou, Haohuan Li, Anan Jiang, Xun Wang, Peng Shang, Mingzhou Li, Keren Long
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引用次数: 0

Abstract

The G0/G1 switch gene 2 (G0s2) is a selective inhibitor of adipose triglyceride lipase (ATGL) which is the rate-limiting enzyme for triglycerides (TGs) hydrolysis in adipocytes, and regulates the mobilization of TGs in adipocytes and hepatocytes. The expression and functional disorders of G0S2 are associated with various metabolic diseases and related pathological states, such as obesity and metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). However, the extent to which the transcriptional regulatory mechanisms mediated by the interaction between the G0s2 gene promoter and enhancer regions are involved remains unknown. Here, through the analysis of epigenomic data (H3K27ac, H3K4me1, and DHS-seq) and luciferase reporter assays, we identified three active enhancers of G0s2 in 3 T3-L1 adipocytes. Subsequently, using the dCas9-KRAB system for epigenetic inhibition of G0S2-En2, -En4, and -En5 revealed the functional role of these enhancers in regulating G0s2 expression and lipid droplet biosynthesis. Additionally, transcriptome analyses revealed that inhibition of G0S2-En5 downregulated pathways associated with lipid metabolism and lipid biosynthesis. Furthermore, overexpression of transcription factors (TFs) and motif mutation experiments identified that PPARG and RXRA regulate the activity of G0S2-En5. Taken together, we identified functional enhancers regulating G0s2 expression and elucidated the important role of the G0S2-En5 in lipid droplet biogenesis.

G0/G1转换基因2(G0S2)是脂肪甘油三酯脂肪酶(ATGL)的选择性抑制剂,而ATGL是脂肪细胞中甘油三酯(TGs)水解的限速酶,并调节脂肪细胞和肝细胞中TGs的动员。G0S2 的表达和功能紊乱与各种代谢性疾病和相关病理状态有关,如肥胖和代谢综合征以及非酒精性脂肪肝(NAFLD)。然而,G0s2 基因启动子和增强子区域之间的相互作用所介导的转录调控机制在多大程度上参与其中仍然未知。在这里,我们通过分析表观基因组数据(H3K27ac、H3K4me1和DHS-seq)和荧光素酶报告实验,在3个T3-L1脂肪细胞中发现了G0s2的三个活性增强子。随后,利用 dCas9-KRAB 系统对 G0S2-En2、-En4 和 -En5 进行表观遗传抑制,发现了这些增强子在调控 G0s2 表达和脂滴生物合成中的功能作用。此外,转录组分析表明,抑制 G0S2-En5 会下调与脂质代谢和脂质生物合成相关的通路。此外,转录因子(TF)的过表达和基因突变实验发现,PPARG 和 RXRA 可调控 G0S2-En5 的活性。综上所述,我们发现了调控 G0s2 表达的功能增强子,并阐明了 G0S2-En5 在脂滴生物生成过程中的重要作用。
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来源期刊
Gene
Gene 生物-遗传学
CiteScore
6.10
自引率
2.90%
发文量
718
审稿时长
42 days
期刊介绍: Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.
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