Multiple Roles for the Non-Coding RNA SRA in Regulation of Adipogenesis and Insulin Sensitivity

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master transcriptional regulator of adipogenesis. Hence, the identification of PPARγ coactivators should help reveal mechanisms controlling gene expression in adipose tissue development and physiology. We show that the non-coding RNA, Steroid receptor RNA Activator (SRA), associates with PPARγ and coactivates PPARγ-dependent reporter gene expression. Overexpression of SRA in ST2 mesenchymal precursor cells promotes their differentiation into adipocytes. Conversely, knockdown of endogenous SRA inhibits 3T3-L1 preadipocyte differentiation. Microarray analysis reveals hundreds of SRA-responsive genes in adipocytes, including genes involved in the cell cycle, and insulin and TNFα signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPARγ. SRA in adipocytes increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. SRA promotes S-phase entry during mitotic clonal expansion, decreases expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, and increases phosphorylation of Cdk1/Cdc2. SRA also inhibits the expression of adipocyte-related inflammatory genes and TNFα-induced phosphorylation of c-Jun NH2-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways.

Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients

“…Of these lncRNAs, SRA and GAS5 are two wellcharacterized lncRNAs that play roles in the endocrine system by mediating their functions as regulators of nuclear receptor (NR) signaling. SRA modulates the effects of steroid hormones on physiology and development [44], while GAS5 lncRNA regulates glucocorticoid signaling in metabolic and inflammatory pathways [45]. Unlike SRA and GAS5, which have been linked to many NRs, another lncRNA, CTBP1-AS, is an androgen-responsive (AR) lncRNA and associated with the AR signaling pathway [46].…”

SRA Gene Knockout Protects against Diet-induced Obesity and Improves Glucose Tolerance

“…Total RNAs from WAT, brown adipose tissue (BAT), liver and skeletal muscle were isolated using TRIzol reagent followed by treatment with DNase I (Qiagen). RT-qPCR analysis of gene expression was as described previously (21,26). Primers are listed in Table 1.…”

“…We have recently shown that SRA promotes adipocyte differentiation and improves insulin-stimulated glucose uptake in adipocytes in vitro through multiple mechanisms, such as coactivating the transcriptional activity of PPAR␥, promoting S-phase entry during mitotic clonal expansion, increasing phosphorylation of Akt/protein kinase B and forkhead box protein O1 (FOXO1) in response to insulin, and inhibiting expression of adipocyte-related inflammatory genes (26). To assess SRA function in vivo, we have generated a whole mouse Sra1 gene knock-out (SRA Ϫ/Ϫ ).…”

The steroid receptor RNA activator protein (SRAP) controls cancer cell migration/motility

“…Since then, many studies have investigated the mechanisms of action of this functional RNA [2][3][4][5][6][7][8]. Through its core sequence (corresponding to exons 2-3-4 and part of exon 5), SRA behaves as a scaffold molecule that physically interacts with a number of RNA binding proteins and transcription factors via specific and critical secondary RNA structures [1][2][3][4]9].…”

“…These SRA-containing complexes involve a wide range of molecules including, but not limited to, multiple nuclear receptors, nuclear receptor co-regulators, and proteins involved in gene silencing and gene insulation [2,3,8,[10][11][12][13]. SRA therefore is believed to be a major transcriptional regulator potentially involved in numerous mechanisms including myogenesis, glucose uptake, tumorigenesis and tumor progression [4,6,[14][15][16][17].…”