Genome-wide Orchestration of Cardiac Functions by the Orphan Nuclear Receptors ERRα and γ

Abstract

Orphan nuclear receptor ERRalpha (NR3B1) is recognized as a key regulator of mitochondrial biogenesis, but it is not known whether ERRalpha and other ERR isoforms play a broader role in cardiac energetics and function. We used genome-wide location analysis and expression profiling to appraise the role of ERRalpha and gamma (NR3B3) in the adult heart. Our data indicate that the two receptors, acting as nonobligatory heterodimers, target a common set of promoters involved in the uptake of energy substrates, production and transport of ATP across the mitochondrial membranes, and intracellular fuel sensing, as well as Ca(2+) handling and contractile work. Motif-finding algorithms assisted by functional studies indicated that ERR target promoters are enriched for NRF-1, CREB, and STAT3 binding sites. Our study thus reveals that the ERRs orchestrate a comprehensive cardiac transcriptional program and further suggests that modulation of ERR activities could be used to manage cardiomyopathies.

Double PHD Fingers Protein DPF2 Recognizes Acetylated Histones and Suppresses the Function of Estrogen-related Receptor α through Histone Deacetylase 1

“…ChIP analysis was performed using the ChIP assay kit (Upstate Biotechnology) according to the manufacturer's instructions. For realtime PCR, we used primer pairs based on a previous report (15). 5Ј-GGAAACAGTTTCTGGCTAGGAATGCGTGA-3Ј and 5Ј-CTGCAAGGGGCAAAGGGTGAGAGGGAGGAGG-3Ј were used for the pyruvate dehydrogenase kinase 4 (PDK4) gene promoter region at ERR␣ response element, and 5Ј-ATG-AGGCGTAGTGCATAACCAA-3Ј and 5Ј-TTGATTGTAGA-GGCGAAAAGACC-3Ј were used for the PDK4 gene distal region.…”

“…However, by functional analysis in cultured cells and intact animals, ERR␣ appears functionally distinct from ER␣ and acts as a regulator in energy metabolism through control of fatty acid oxidation, mitochondrial biogenesis, and oxidative phosphorylation (14). Reflecting the physio-logic role of ERR␣, a number of ERR␣ target genes have been identified (15), and transcriptional function was shown to depend on chromatin environment of the promoters. Although no endogenous ligand has yet been found, synthetic ERR␣ ligands appear to modulate ERR␣ transcriptional activity as inverse antagonists (16,17).…”

Nuclear receptors, mitochondria and lipid metabolism

“…ERRγ is highly expressed in tissues with high metabolic activity (e.g. heart, kidney, slow-twitch muscle, BAT and CNS) and loss of this receptor in mouse results in neonatal death, presumably due to motor defects that prevent feeding Dufour et al 2007). …”

Estrogen-related receptor α participates transforming growth factor-β (TGF-β) induced epithelial-mesenchymal transition of osteosarcoma cells

“…Further studies indicated that ERRa can bind to and activate transcription through ERR-response elements (ERREs), which is different from those mediating the estrogenic response (Estrogen Response Elements, EREs). 9 ERRa can directly regulate tumor progression of various cancer cells via modulation of cell motility. Studies indicated that over expression of ERRa in xenografted breast cancer cells increases their metastatic capacities.…”