Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology.
Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology. The nuclear receptor corepressor 1 (Ncor1) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (Hdac3). Lack of Ncor1 is incompatible with life, and hence it is unknown whether Ncor1, and particularly its regulation of Hdac3, is critical for adult mammalian physiology. Here we show that specific, genetic disruption of the Ncor1-Hdac3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behaviour. These mice are also leaner and more insulin-sensitive owing to increased energy expenditure. Unexpectedly, loss of a functional Ncor1-Hdac3 complex in vivo does not lead to sustained increases in known catabolic genes, but instead significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of Hdac3 by Ncor1 is a nodal point in the epigenetic regulation of circadian and metabolic physiology.
Alenghat
Theresa
T
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Meyers
Katherine
K
Mullican
Shannon E
SE
Leitner
Kirstin
K
Adeniji-Adele
Adetoun
A
Avila
Jacqueline
J
Bućan
Maja
M
Ahima
Rexford S
RS
Kaestner
Klaus H
KH
Lazar
Mitchell A
MA
D056930:ARNTL Transcription Factors; D019943:Amino Acid Substitution; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004032:Diet; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D006655:Histone Deacetylases; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C431792:Arntl2 protein, mouse; C539128:Ncor1 protein, mouse