The master energy homeostasis regulator PGC-1α exhibits a novel mRNA nuclear export function [ChIP-Seq]

PGC-1α 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-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α 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-1α-binding promoters, identifyingin turnnovel mRNA nuclear export targets inmRNA- and age-related pathways.These findingsprovide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing andneurodegeneration. Comparative chromatin immuniprecipitation DNA seqeuncing (ChIP-seq) analysis using data from 18 samples from stable inducible Flp-In T-REx 293 cell lines. The cells lines included (i) Sham - a negative control line which has undergone the same procedures for generation of stable inducible cell lines but does not have a GOI inserted; (ii) PGC-1α WT-res - a cell line with endogenous depletion of PGC-1α and replacement with wild-type cDNA; (iii) PGC-1α ΔRS-res - a cell line with endogenous depletion of PGC-1α and replacement with deletion construct of PGC-1α lacking amino acids 595-633. For each group, cells from three consecutive passages were used.