Identification of a chromatin-bound ERRα interactome network in mouse liver

Abstract

ObjectiveEstrogen-related-receptor (ERR) plays a critical role in the transcriptional regulation of cellular bioenergetics and metabolism, and perturbations in its activity have been associated with metabolic diseases. While several coactivators and corepressors of ERR have been identified to date, a knowledge gap remains in understanding the extent to which ERR cooperates with coregulators in the control of gene expression. Herein, we mapped the primary chromatin-bound ERR interactome in mouse liver. MethodsRIME (Rapid Immuno-precipitation Mass spectrometry of Endogenous proteins) analysis using mouse liver samples from two circadian time points was used to catalog ERR-interacting proteins on chromatin. The genomic crosstalk between ERR and its identified cofactors in the transcriptional control of precise gene programs was explored through cross-examination of genome-wide binding profiles from chromatin immunoprecipitation-sequencing (ChIP-seq) studies. The dynamic interplay between ERR and its newly uncovered cofactor Host cell factor C1 (HCFC1) was further investigated by loss-of-function studies in hepatocytes. ResultsCharacterization of the hepatic ERR chromatin interactome led to the identification of 48 transcriptional interactors of which 42 were previously unknown including HCFC1. Interrogation of available ChIP-seq binding profiles highlighted oxidative phosphorylation (OXPHOS) under the control of a complex regulatory network between ERR and multiple cofactors. While ERR and HCFC1 were found to bind to a large set of common genes, only a small fraction showed their co-localization, found predominately near the transcriptional start sites of genes particularly enriched for components of the mitochondrial respiratory chain. Knockdown studies demonstrated inverse regulatory actions of ERR and HCFC1 on OXPHOS gene expression ultimately dictating the impact of their loss-of-function on mitochondrial respiration. ConclusionsOur work unveils a repertoire of previously unknown transcriptional partners of ERR comprised of chromatin modifiers and transcription factors thus advancing our knowledge of how ERR regulates metabolic transcriptional programs.