title: Class IIa histone deacetylases are conserved regulators of circadian function.
abstract: Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca(2+) and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery.
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and.
authors.forename: Paul C M
authors.initials: PC
authors.lastname: Fogg
authors.affiliation: the Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
authors.forename: John S
authors.initials: JS
authors.lastname: O'Neill
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Dobrzycki
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and.
authors.forename: Shaun
authors.initials: S
authors.lastname: Calvert
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Lord
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and.
authors.forename: Rebecca L L
authors.initials: RL
authors.lastname: McIntosh
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and.
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Elliott
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Sweeney
authors.affiliation: the Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hastings
authors.affiliation: From the Department of Biology, University of York, York YO10 5DD, United Kingdom and sangeeta.chawla@york.ac.uk.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Chawla
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D057906:Circadian Clocks / Q000235:genetics*; D017124:Conserved Sequence; D000242:Cyclic AMP; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C120526:Clk protein, Drosophila; D029721:Drosophila Proteins; D056572:Histone Deacetylase Inhibitors; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000242:Cyclic AMP; D008156:Luciferases; D056926:CLOCK Proteins; C559672:HDAC4 protein, Drosophila; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D002118:Calcium
keywords: Circadian Rhythm; Clock Gene; Drosophila; Histone Deacetylase (HDAC); Nuclear Translocation