To address this issue, we analyzed independent genome-wide datasets and found that CLOCK:BMAL1 DNA binding during the day is associated with a reorganization of the chromatin that is favorable to transcription activation for all target genes. 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. 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.Ĭircadian clocks in mammals rely on the heterodimeric transcription factor CLOCK:BMAL1 to drive rhythmic gene expression and allow biological functions to perform best at the most appropriate time of the day. 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. 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. 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.

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. 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. 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.

Target clocks