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TRNA-derived small non-coding RNAs as novel epigenetic molecules regulating adipogenesis

ABSTRACT: tRNA-derived fragments (tRFs) are a novel class of non-coding RNA that play an vital role in regulating gene expression at post-transcriptional level. To date, it is completely unknown the regulatory mechanism of tRFs governing fat deposition and adipogenesis. In this study, we used high fat diet successfully induced obese rat model, and used tRFs transcriptome sequencing to select differentially expressed tRFs that response to obesity. We found tRFGluTTC was the highest fold change in the 296 differentially expressed tRFs, which promoted preadipocytes proliferation by increasing the expression of cell cycle regulatory factors. Moreover, tRFGluTTC also suppressed preadipocytes differentiation by reducing lipid accumulation and triglyceride content, and decreasing the expression of genes related to fatty acid synthesis. According to luciferase activity assays, tRFGluTTC directly targeted KLF9, KLF11, and KLF12, and could significantly suppressed the mRNA expression of these target genes. Besides, tRFGluTTC suppressed adipogenesis also accompanied by decreasing the expression of adipogenic transcription factors (AP2, C/EBPα, and PPARγ). Taken together, these results imply that tRFGluTTC may take as a novel epigenetic molecules governing adipogenesis and could be a target for therapeutic intervention in obesity.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE129685 | GEO | 2019/04/12

REPOSITORIES: GEO

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Project description:Visceral fat (VF) and subcutaneous fat (SF) are developmentally different tissues with different gene expression. Islet-1 (ISL1), a LIM-homeobox transcription factor with important developmental and regulatory function in islet, neural, and cardiac tissue, is virtually absent in SF but substantially expressed in the stromovascular [preadipocyte containing] fraction of VF; expression correlates negatively with adiposity in rodents and man. ISL1 expression is transiently increased in 3T3-L1 preadipocytes during early differentiation, suggesting a functional role. To examine the role of ISL1 in adipogenesis, we tested whether retroviral overexpression of ISL1 in 3T3-L1 preadipocytes affected their ability to differentiate into mature adipocytes. Terminal differentiation was assessed by Oil Red O [lipid droplet] staining and by immunoblot detection of adipocyte marker proteins, including aP2 and GLUT4. ISL1 significantly inhibited lipid droplet formation, reduced lipid accumulation (about 80% inhibition, p<0.05), and substantially inhibited aP2 and GLUT4 expression. ISL1 did not inhibit expression of C/EBPb and C/EBPd after induction of differentiation, but reduced PPARg and C/EBPa by >50% at both mRNA and protein level. In addition, the PPARg agonist, rosiglitazone, substantially rescued ISL1 inhibited adipogenesis in the absence of exogenous PPARg, and fully rescued in the presence of exogenous PPARg. In summary, ISL1 overexpression inhibited fat droplet formation, lipid accumulation, and adipocyte-specific gene expression; there was accompanying inhibition of C/EBPa, PPARg and downstream gene expression. We conclude that ISL1 overexpression inhibited adipocyte differentiation by inhibition of PPARg regulated gene expression. As abdominal obesity strongly correlates with insulin resistance, and cardiovascular risk, ISL1 up-regulation may impact abdominal obesity and its concomitant metabolic derangements. Total cellular RNA was isolated from 3T3-L1 cells expressing Flag-ISL1 or not at 48 h following treatment with differentiation cocktail. Individual RNA from biological triplicates was used for microarray analysis.

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TRNA-derived small non-coding RNAs as novel epigenetic molecules regulating adipogenesis

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