Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms
| Autor: | Andrew C. Liu, Eric E. Zhang, Steve A. Kay, David K. Welsh, Aaron A. Priest, Hien G. Tran |
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| Přispěvatelé: | Takahashi, Joseph S |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Transcription Genetic Cytoplasmic and Nuclear Circadian clock Messenger Receptors Cytoplasmic and Nuclear Transgenic Mice 0302 clinical medicine Group D Cryptochrome RAR-related orphan receptor gamma Models Receptors Transcriptional regulation Basic Helix-Loop-Helix Transcription Factors Tissue Distribution Genetics (clinical) Mice Knockout Genetics Regulation of gene expression 0303 health sciences Neuroscience/Behavioral Neuroscience ARNTL Transcription Factors Cell biology Circadian Rhythm Genetics and Genomics/Gene Function PER2 DNA-Binding Proteins Liver Sleep Research Transcription Research Article Signal Transduction endocrine system Member 1 lcsh:QH426-470 Nuclear Receptor Subfamily 1 Knockout 1.1 Normal biological development and functioning Mice Transgenic Biology Models Biological Feedback 03 medical and health sciences Genetic Underpinning research Animals RNA Messenger Circadian rhythm Molecular Biology Cell Biology/Gene Expression Ecology Evolution Behavior and Systematics 030304 developmental biology Flavoproteins Fibroblasts Biological Repressor Proteins Cryptochromes lcsh:Genetics Nuclear Receptor Subfamily 1 Group D Member 1 RNA 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS genetics, vol 4, iss 2 PLoS Genetics, Vol 4, Iss 2, p e1000023 (2008) PLoS Genetics Liu, AC; Tran, HG; Zhang, EE; Priest, AA; Welsh, DK; & Kay, SA. (2008). Redundant function of REV-ERBα and β and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genetics, 4(2). doi: 10.1371/journal.pgen.1000023. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/8m7647dj |
| DOI: | 10.1371/journal.pgen.1000023. |
| Popis: | The mammalian circadian clockwork is composed of a core PER/CRY feedback loop and additional interlocking loops. In particular, the ROR/REV/Bmal1 loop, consisting of ROR activators and REV-ERB repressors that regulate Bmal1 expression, is thought to “stabilize” core clock function. However, due to functional redundancy and pleiotropic effects of gene deletions, the role of the ROR/REV/Bmal1 loop has not been accurately defined. In this study, we examined cell-autonomous circadian oscillations using combined gene knockout and RNA interference and demonstrated that REV-ERBα and β are functionally redundant and are required for rhythmic Bmal1 expression. In contrast, the RORs contribute to Bmal1 amplitude but are dispensable for Bmal1 rhythm. We provide direct in vivo genetic evidence that the REV-ERBs also participate in combinatorial regulation of Cry1 and Rorc expression, leading to their phase-delay relative to Rev-erbα. Thus, the REV-ERBs play a more prominent role than the RORs in the basic clock mechanism. The cellular genetic approach permitted testing of the robustness of the intracellular core clock function. We showed that cells deficient in both REV-ERBα and β function, or those expressing constitutive BMAL1, were still able to generate and maintain normal Per2 rhythmicity. Our findings thus underscore the resilience of the intracellular clock mechanism and provide important insights into the transcriptional topologies underlying the circadian clock. Since REV-ERB function and Bmal1 mRNA/protein cycling are not necessary for basic clock function, we propose that the major role of the ROR/REV/Bmal1 loop and its constituents is to control rhythmic transcription of clock output genes. Author Summary Circadian clocks in plants, fungi, insects, and mammals all share a common transcriptional network architecture. At the cellular level, the mammalian clockwork consists of a core Per/Cry negative feedback loop and additional interlocking loops. We wished to address experimentally the contribution of the interlocking Bmal1 loop to clock function in mammals. Because behavioral rhythms do not always reflect cell-autonomous phenotypes and are subject to pleiotropic effects, we employed cell-based genetic approaches and monitored rhythms longitudinally using bioluminescent reporters of clock gene expression. We showed that REV-ERB repressors play a more prominent role than ROR activators in regulating the Bmal1 rhythm. However, significant rhythmicity remains even with constitutive expression of Bmal1, pointing to the resilience of the core loop to perturbations of the Bmal1 loop. We conclude that while the interlocking loop contributes to fine-tuning of the core loop, its primary function is to provide discrete waveforms of clock gene expression for control of local physiology. This study has important general implications not only for circadian biology across species, but also for the emerging field of systems biology that seeks to understand complex interactions in genetic networks. |
| Databáze: | OpenAIRE |
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