Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma.
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.
Dufour
Catherine R
CR
Molecular Oncology Group, McGill University Health Centre, Montréal, Québec H3A 1A1, Canada.
Wilson
Brian J
BJ
Huss
Janice M
JM
Kelly
Daniel P
DP
Alaynick
William A
WA
Downes
Michael
M
Evans
Ronald M
RM
Blanchette
Mathieu
M
Giguère
Vincent
V
D000818:Animals; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome / Q000235:genetics*; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051265:NF-E2-Related Factor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
D017362:Cyclic AMP Response Element-Binding Protein; D051265:NF-E2-Related Factor 1; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D050796:STAT3 Transcription Factor; D000097983:ERRalpha Estrogen-Related Receptor; C492004:Creb1 protein, mouse; C490917:ESRRG protein, human; C494087:Stat3 protein, mouse