Crosstalk interactions between transcription factors ERRα and PPARα assist PPARα-mediated gene expression

Abstract

AbstractThe peroxisome proliferator-activated receptor α (PPARα) is a crucial transcription factor governing genes associated with fatty acid β-oxidation. How various interacting proteins modulate PPARα’s transcriptional function remains incompletely understood. Employing an unbiased mammalian protein-protein interaction trap with liganded PPARα as bait, we identified an interaction with the orphan nuclear receptor estrogen-related receptor α (ERRα). Random mutagenesis scanning of PPARα’s ligand-binding domain and coregulator profiling experiments implicated bridging coregulators, whilein vitrostudies suggested a trimeric interaction involving RXRα. The PPARα·ERRα interaction, dependent on three C-terminal residues within ERRα’s helix 12, was reinforced by PGC1α and serum deprivation. Pharmacological inhibition of ERRα reduced its interaction with ligand-activated PPARα, revealing a transcriptome indicative of ERRα functioning as a transcriptional repressor on prototypical PPARα target genes. Intriguingly, ERRα exhibited opposite behavior on other PPARα targets, including the isolated PDK4 enhancer. Chromatin immunoprecipitation analyses demonstrated PPARα ligand-dependent recruitment of ERRα onto specific chromatin regions where PPARα binds in mouse livers. These findings highlight intricate transcriptional crosstalk mechanisms between PPARα and ERRα, suggesting a multi-layered regulatory network fine-tuning PPARα’s activity as a nutrient-sensing transcription factor.