Peroxisome proliferator-activated receptor alpha-mediated regulation of long non-coding RNA and the potential influence on lipid homeostasis

FARE Award Winner

Authors

• CN Brocker
• T Melia
• JA Bonzo
• DJ Waxman
• FJ Gonzalez

Abstract

The advent of deep sequencing has revealed that the transcriptional landscape of the genome is overwhelming complex. One of the most striking observations is that only one-fifth of transcriptome is attributed to coding genes with the remaining made up of non-coding RNA (ncRNA). Long ncRNAs (lncRNA) represent a relatively unstudied group of ncRNA with diverse functions within the cell. Peroxisome proliferator-activated receptor alpha (PPARA) is a nuclear receptor and major regulator of lipid metabolism. PPARA and downstream genes represent important targets for treating metabolic diseases including hyperlipidemia and obesity. While PPARA activates expression of many targets, it also suppresses expression of select genes. We hypothesized that this is due to transrepression possibly involving lncRNAs. RNAseq was performed on livers from mice treated with PPARA agonist. Analysis revealed 2557 putative lncRNA species. Of these, 523 were robustly regulated in response to agonist. lncRNA levels did not correlate with neighboring genes indicating lncRNA are expressed as independent transcriptional units. PPARA-mediated changes in differentially regulated lncRNA were confirmed by qRT-PCR. Analysis of PPARA knockout mice indicated that expression was PPARA-dependent. Monitoring RNA levels after activation revealed that expression profiles paralleled coding target genes. Promoter regions from PPARA ChIPseq datasets were screened for binding sites. All promoters analyzed exhibited binding peaks that were supported by sites computationally predicted. This study provides preliminary evidence for the direct regulation of lncRNA by PPARA, suggesting that these RNA may play important roles during lipid homeostasis and possible function in transrepression of gene expression by PPARA activation.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Friday, March 26, 2021