Rhythmic PER Abundance Defines a Critical Nodal Point for Negative Feedback within the Circadian Clock Mechanism

Rongmin Chen, Aaron Schirmer, Yongjin Lee, Hyeongmin Lee, Vivek Kumar, Seung Hee Yoo, Joseph S. Takahashi, Choogon Lee

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Circadian rhythms in mammals are generated by a transcriptional negative feedback loop that is driven primarily by oscillations of PER and CRY, which inhibit their own transcriptional activators, CLOCK and BMAL1. Current models posit that CRY is the dominant repressor, while PER may play an accessory role. In this study, however, constitutive expression of PER, and not CRY1, severely disrupted the clock in fibroblasts and liver. Furthermore, constitutive expression of PER2 in the brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. These results demonstrate that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and in the intact organism. Our biochemical evidence supports an elegant mechanism for the disparity: PER2 directly and rhythmically binds to CLOCK:BMAL1, while CRY only interacts indirectly; PER2 bridges CRY and CLOCK:BMAL1 to drive the circadian negative feedback loop.

Original languageEnglish (US)
Pages (from-to)417-430
Number of pages14
JournalMolecular Cell
Volume36
Issue number3
DOIs
StatePublished - Nov 13 2009

Fingerprint

Circadian Clocks
Circadian Rhythm
Transgenic Mice
Mammals
Fibroblasts
Liver
Brain

Keywords

  • MOLNEURO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Rhythmic PER Abundance Defines a Critical Nodal Point for Negative Feedback within the Circadian Clock Mechanism. / Chen, Rongmin; Schirmer, Aaron; Lee, Yongjin; Lee, Hyeongmin; Kumar, Vivek; Yoo, Seung Hee; Takahashi, Joseph S.; Lee, Choogon.

In: Molecular Cell, Vol. 36, No. 3, 13.11.2009, p. 417-430.

Research output: Contribution to journalArticle

Chen, Rongmin ; Schirmer, Aaron ; Lee, Yongjin ; Lee, Hyeongmin ; Kumar, Vivek ; Yoo, Seung Hee ; Takahashi, Joseph S. ; Lee, Choogon. / Rhythmic PER Abundance Defines a Critical Nodal Point for Negative Feedback within the Circadian Clock Mechanism. In: Molecular Cell. 2009 ; Vol. 36, No. 3. pp. 417-430.
@article{2951b4430a7f4dc5bcaa9e42ed4edf68,
title = "Rhythmic PER Abundance Defines a Critical Nodal Point for Negative Feedback within the Circadian Clock Mechanism",
abstract = "Circadian rhythms in mammals are generated by a transcriptional negative feedback loop that is driven primarily by oscillations of PER and CRY, which inhibit their own transcriptional activators, CLOCK and BMAL1. Current models posit that CRY is the dominant repressor, while PER may play an accessory role. In this study, however, constitutive expression of PER, and not CRY1, severely disrupted the clock in fibroblasts and liver. Furthermore, constitutive expression of PER2 in the brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. These results demonstrate that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and in the intact organism. Our biochemical evidence supports an elegant mechanism for the disparity: PER2 directly and rhythmically binds to CLOCK:BMAL1, while CRY only interacts indirectly; PER2 bridges CRY and CLOCK:BMAL1 to drive the circadian negative feedback loop.",
keywords = "MOLNEURO, PROTEINS, SIGNALING",
author = "Rongmin Chen and Aaron Schirmer and Yongjin Lee and Hyeongmin Lee and Vivek Kumar and Yoo, {Seung Hee} and Takahashi, {Joseph S.} and Choogon Lee",
year = "2009",
month = "11",
day = "13",
doi = "10.1016/j.molcel.2009.10.012",
language = "English (US)",
volume = "36",
pages = "417--430",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Rhythmic PER Abundance Defines a Critical Nodal Point for Negative Feedback within the Circadian Clock Mechanism

AU - Chen, Rongmin

AU - Schirmer, Aaron

AU - Lee, Yongjin

AU - Lee, Hyeongmin

AU - Kumar, Vivek

AU - Yoo, Seung Hee

AU - Takahashi, Joseph S.

AU - Lee, Choogon

PY - 2009/11/13

Y1 - 2009/11/13

N2 - Circadian rhythms in mammals are generated by a transcriptional negative feedback loop that is driven primarily by oscillations of PER and CRY, which inhibit their own transcriptional activators, CLOCK and BMAL1. Current models posit that CRY is the dominant repressor, while PER may play an accessory role. In this study, however, constitutive expression of PER, and not CRY1, severely disrupted the clock in fibroblasts and liver. Furthermore, constitutive expression of PER2 in the brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. These results demonstrate that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and in the intact organism. Our biochemical evidence supports an elegant mechanism for the disparity: PER2 directly and rhythmically binds to CLOCK:BMAL1, while CRY only interacts indirectly; PER2 bridges CRY and CLOCK:BMAL1 to drive the circadian negative feedback loop.

AB - Circadian rhythms in mammals are generated by a transcriptional negative feedback loop that is driven primarily by oscillations of PER and CRY, which inhibit their own transcriptional activators, CLOCK and BMAL1. Current models posit that CRY is the dominant repressor, while PER may play an accessory role. In this study, however, constitutive expression of PER, and not CRY1, severely disrupted the clock in fibroblasts and liver. Furthermore, constitutive expression of PER2 in the brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. These results demonstrate that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and in the intact organism. Our biochemical evidence supports an elegant mechanism for the disparity: PER2 directly and rhythmically binds to CLOCK:BMAL1, while CRY only interacts indirectly; PER2 bridges CRY and CLOCK:BMAL1 to drive the circadian negative feedback loop.

KW - MOLNEURO

KW - PROTEINS

KW - SIGNALING

UR - http://www.scopus.com/inward/record.url?scp=70449093653&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70449093653&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2009.10.012

DO - 10.1016/j.molcel.2009.10.012

M3 - Article

VL - 36

SP - 417

EP - 430

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -