title: A novel protein, CHRONO, functions as a core component of the mammalian circadian clock.
abstract: Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. We have recently identified Chrono as a robustly cycling transcript through genome-wide profiling of BMAL1 binding on the E-box. Here, we explore the role of Chrono in cellular timekeeping. Remarkably, endogenous CHRONO occupancy around E-boxes shows a circadian oscillation antiphasic to BMAL1. Overexpression of Chrono leads to suppression of BMAL1-CLOCK activity in a histone deacetylase (HDAC) -dependent manner. In vivo loss-of-function studies of Chrono including Avp neuron-specific knockout (KO) mice display a longer circadian period of locomotor activity. Chrono KO also alters the expression of core clock genes and impairs the response of the circadian clock to stress. CHRONO forms a complex with the glucocorticoid receptor and mediates glucocorticoid response. Our comprehensive study spotlights a previously unrecognized clock component of an unsuspected negative circadian feedback loop that is independent of another negative regulator, Cry2, and that integrates behavioral stress and epigenetic control for efficient metabolic integration of the clock.
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama, Japan; Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Goriki
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama, Japan; Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Hatanaka
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama, Japan; Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Jihwan
authors.initials: J
authors.lastname: Myung
authors.affiliation: Department of Mathematics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jae Kyoung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoritaka
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Tanoue
authors.affiliation: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Chuo, Kobe, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.affiliation: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Chuo, Kobe, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fujimoto
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Todo
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsubara
authors.affiliation: Department of Mathematics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Forger
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama, Japan; Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
mesh_terms: D016475:3T3 Cells; D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C587926:Ciart protein, mouse; D056925:Circadian Rhythm Signaling Peptides and Proteins; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D006655:Histone Deacetylases
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