Abstract
The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of 15% of the transcriptome and control the daily regulation of biological functions. The recent characterization of CLOCK:BMAL1 cistrome revealed that although CLOCK:BMAL1 binds synchronously to all of its target genes, its transcriptional output is highly heterogeneous. By performing a meta-analysis of several independent genome-wide datasets, we found that the binding of other transcription factors at CLOCK:BMAL1 enhancers likely contribute to the heterogeneity of CLOCK:BMAL1 transcriptional output. While CLOCK:BMAL1 rhythmic DNA binding promotes rhythmic nucleosome removal, it is not sufficient to generate transcriptionally active enhancers as assessed by H3K27ac signal, RNA Polymerase II recruitment, and eRNA expression. Instead, the transcriptional activity of CLOCK:BMAL1 enhancers appears to rely on the activity of ubiquitously expressed transcription factors, and not tissue-specific transcription factors, recruited at nearby binding sites. The contribution of other transcription factors is exemplified by how fasting, which effects several transcription factors but not CLOCK:BMAL1, either decreases or increases the amplitude of many rhythmically expressed CLOCK:BMAL1 target genes. Together, our analysis suggests that CLOCK:BMAL1 promotes a transcriptionally permissive chromatin landscape that primes its target genes for transcription activation rather than directly activating transcription, and provides a new framework to explain how environmental or pathological conditions can reprogram the rhythmic expression of clock-controlled genes.
Highlights
Every mammalian cell harbors a circadian clock that regulates rhythmic gene expression to enable biological functions to occur at the most appropriate time of day
Investigation of the mechanisms by which CLOCK:BMAL1 regulates its target genes transcription has led to the paradoxical observation that while CLOCK:BMAL1 DNA binding is rhythmic and occurs during the day for all target genes, its transcriptional output is highly heterogeneous
To characterize the mechanisms by which CLOCK:BMAL1 regulates the transcriptional activity of its target genes at the genome-wide level in the mouse liver, we first generated a list of high-confidence CLOCK:BMAL1 DNA binding sites by determining the overlap between CLOCK and BMAL1 ChIP-Seq peaks in the mouse liver [3]
Summary
Every mammalian cell harbors a circadian clock that regulates rhythmic gene expression to enable biological functions to occur at the most appropriate time of day. CLOCK:BMAL1 rhythmically binds to DNA to activate the rhythmic transcription of the core clock genes Period (Per, Per, Per3), Cryptochrome (Cry and Cry2), Rev-erb (Rev-erbα and Rev-erbβ) and Ror (Rorα, Rorβ and Rorγ). PERs and CRYs form a repressive complex that rhythmically inhibits CLOCK:BMAL1-mediated transcription first on-DNA and offDNA [2,3,4,5]. REV-ERBs and RORs rhythmically regulate Bmal expression by repressing or activating its transcription, which promotes robustness of circadian oscillations [6, 7]. In addition to activating the rhythmic transcription of core clock components, CLOCK: BMAL1 regulates rhythmic expression of thousands of clock-controlled genes to generate oscillations in biochemistry, physiology and behavior, and control the rhythmic organization of most biological functions [8,9,10]
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