A novel protein, CHRONO, functions as a core component of the mammalian circadian clock

PLoS Biol. 2014 Apr 15;12(4):e1001839. doi: 10.1371/journal.pbio.1001839. eCollection 2014 Apr.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3 Cells
  • ARNTL Transcription Factors / metabolism*
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Circadian Clocks / genetics
  • Circadian Clocks / physiology*
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology
  • Circadian Rhythm Signaling Peptides and Proteins / biosynthesis
  • Circadian Rhythm Signaling Peptides and Proteins / genetics
  • Circadian Rhythm Signaling Peptides and Proteins / metabolism*
  • Cryptochromes / genetics
  • Cryptochromes / metabolism*
  • Histone Deacetylases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Receptors, Glucocorticoid / metabolism
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sequence Alignment
  • Transcription, Genetic / genetics

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Circadian Rhythm Signaling Peptides and Proteins
  • Cry1 protein, mouse
  • Cry2 protein, mouse
  • Cryptochromes
  • Gm129 protein, mouse
  • Receptors, Glucocorticoid
  • Repressor Proteins
  • Histone Deacetylases

Grant support

Japan Society of Promotion of Science and Ministry of Education, Culture, Sports, Science, and Technology KAKENHI, Strategic International Coorperative Program and CREST, Japan Science and Technology Agency, Human Frontier Science Program (HFSP) grant RPG 24/2012, the Takeda Science Foundation, Mitsui Life Social Welfare Foundation, Sony Corporation, and Nippon Boehringer Ingelheim Co. NSF grant DMS-0931642 to the Mathematical Biosciences Institute (JKK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.