Homer1a Undergoes Bimodal Transcriptional Regulation by CREB and the Circadian Clock

• Published in: Neuroscience 2020-05, Vol.434, p.161-170
• Main Authors: Sato, Shogo, Bunney, Blynn G., Vawter, Marquis P., Bunney, William E., Sassone-Corsi, Paolo
• Format: Article
• Language: English
• Subjects: Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; BMAL1; Circadian Clocks - genetics; Circadian Rhythm - genetics; circadian rhythms; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; CREB; Gene Expression Regulation; Homer1a; Mice; sleep deprivation
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2020.03.031

•Homer1a, but not the long variant of the Homer1 gene, exhibits robust circadian oscillation in mouse brain.•Circadian oscillation of Homer1a gene is independent of core clock regulator BMAL1.•Response of Homer1a gene to sleep deprivation stress is blunted in the absence of BMAL1.•Phosphorylation of CREB is attenuated in brain of Bmal1-null mice, and is recovered by sleep deprivation stress. Accumulating evidence points to a significant link between disrupted circadian rhythms and neuronal disfunctions, though the molecular mechanisms underlying this connection are virtually unexplored. The transcript Homer1a, an immediate early gene related to postsynaptic signaling, has been demonstrated to exhibit robust circadian oscillation in the brain, which supports the hypothesis that Homer1a mediates the communication between circadian inputs and neuronal activity. Here, we determined how the circadian clock is implicated in Homer1a gene regulation by using circadian clock Bmal1-mutant mice either in the presence or absence of stress stimulation. The Homer1 gene generates multiple transcripts, but only the short variant Homer1a responds to acute stress with sleep deprivation (SD) in mice. Chromatin immunoprecipitation assays revealed that both transcription factor CREB and the circadian clock component BMAL1 bind to the Homer1 promoter in mouse brain. Importantly, circadian Homer1a gene expression is unaltered in the absence of BMAL1, while its immediate early response to SD relies on BMAL1. Deletion of Bmal1 results in attenuated CREB activity in mouse brain, which appears to contribute to decreased expression of Homer1a in response to SD. In conclusion, Homer1a undergoes bimodal control by the circadian clock and CREB.