The master energy homeostasis regulator PGC-1a exhibits a novel mRNA nuclear export function [RNA-Seq]
PGC-1a plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however the potential RNA-processing function(s) remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1a directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1a and expression of RNAi-resistant RS-deleted PGC-1a further demonstrated that its RNA/NXF1-binding activity is required for the nuclear exportof a subset of mRNAsand mitochondrial homeostasis.Genome-wide investigations revealed that the nuclear export function is not strictly linked to PGC-1a-binding promoters, identifyingin turnnovel mRNA nuclear export targets inmRNA- and age-related pathways.These findingsprovide new directions to further elucidate the roles of PGC-1a in gene expression, metabolic disorders, ageing andneurodegeneration. Overall design: Comparative gene expression analysis using RNA-seq data from 12 samples from stable inducible Flp-In T-REx 293 cell lines. We used whole-cell (total; WCT) RNA and cytoplasmic fraction (CyT) RNA for each cell line. The cells lines included (i) PGC-1a WT-res - a cell line with endogenous depletion of PGC-1a and replacement with wild-type cDNA; (ii) PGC-1a ?RS-res - a cell line with endogenous depletion of PGC-1a and replacement with deletion construct of PGC-1a lacking amino acids 595-633. For each group, cells from three consecutive passages were used.