TY - JOUR

T1 - Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

AU - Bugge, Anne Skovsø

AU - Feng, Dan

AU - Everett, Logan J

AU - Briggs, Erika R

AU - Mullican, Shannon E

AU - Wang, Fenfen

AU - Jager, Jennifer

AU - Lazar, Mitchell A

PY - 2012/4/1

Y1 - 2012/4/1

N2 - The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.

AB - The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.

KW - Animals

KW - Cells, Cultured

KW - Circadian Rhythm

KW - Gene Expression Regulation

KW - Genome

KW - Histone Deacetylases

KW - Liver

KW - Mice

KW - Mice, Inbred C57BL

KW - Nuclear Receptor Co-Repressor 1

KW - Nuclear Receptor Subfamily 1, Group D, Member 1

KW - RNA, Messenger

KW - Receptors, Cytoplasmic and Nuclear

KW - Repressor Proteins

U2 - 10.1101/gad.186858.112

DO - 10.1101/gad.186858.112

M3 - Journal article

C2 - 22474260

VL - 26

SP - 657

EP - 667

JO - Genes & Development

JF - Genes & Development

SN - 0890-9369

IS - 7

ER -