Homer1a Undergoes Bimodal Transcriptional Regulation by CREB and the Circadian Clock

📖 Top 20% JournalMar 31, 2020Neuroscience

Homer1a Gene Is Controlled in Two Ways by CREB and the Body’s Internal Clock

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Abstract

Homer1a gene expression is regulated by the circadian clock and is significantly affected by stress.

Disrupted circadian rhythms may be linked to neuronal dysfunctions, though underlying molecular mechanisms are largely unexplored.
The Homer1 gene produces several transcripts, with the short variant Homer1a specifically responding to acute stress from sleep deprivation in mice.
Both the transcription factor CREB and the circadian clock component BMAL1 bind to the Homer1 promoter in mouse brain.
Circadian expression of Homer1a remains stable without BMAL1, but its stress-related response is dependent on BMAL1.
Loss of Bmal1 leads to reduced CREB activity, which may result in lower Homer1a expression in response to sleep deprivation.

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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.

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