redundant function of rev-erbα and β and non-essential role for bmal1 cycling in transcriptional regulation of intracellular circadian rhythms冗余的函数rev-erbαβ和不必要的角色bmal1自行车在细胞内的转录调节昼夜节律.pdfVIP

Redundant Function of REV-ERBa and b and Non-Essential Role for Bmal1 Cycling in Transcriptional Regulation of Intracellular Circadian Rhythms 1,2 1,2 1,2 1 1,3,4 1 Andrew C. Liu , Hien G. Tran , Eric E. Zhang , Aaron A. Priest , David K. Welsh , Steve A. Kay * 1 Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America, 2 Genomics Institute, Novartis Research Foundation, San Diego, California, United States of America, 3 Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America, 4 Veterans Affairs, San Diego Healthcare System, San Diego, California, United States of America Abstract 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-ERBa and b 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-erba. Thus, the REV-ERBs