The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of thousands of genes. Consistent with the various biological functions under clock control, rhythmic gene expression is tissue-specific despite an identical clockwork mechanism in every cell. Here we show that BMAL1 DNA binding is largely tissue-specific, likely because of differences in chromatin accessibility between tissues and cobinding of tissue-specific transcription factors. Our results also indicate that BMAL1 ability to drive tissue-specific rhythmic transcription is associated with not only the activity of BMAL1-bound enhancers but also the activity of neighboring enhancers. Characterization of physical interactions between BMAL1 enhancers and other cis-regulatory regions by RNA polymerase II chromatin interaction analysis by paired-end tag (ChIA-PET) reveals that rhythmic BMAL1 target gene expression correlates with rhythmic chromatin interactions. These data thus support that much of BMAL1 target gene transcription depends on BMAL1 capacity to rhythmically regulate a network of enhancers.

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Circadian clocks regulate the rhythmic expression of thousands of genes underlying the daily oscillations of biological functions. Here, we discuss recent findings showing that circadian clock rhythmic transcriptional outputs rely on additional mechanisms than just clock gene DNA binding, which may ultimately contribute to the plasticity of circadian transcriptional programs.

SummaryAlternative polyadenylation (APA) generates transcript isoforms with different 3’ ends. Differences in polyadenylation sites usage, which have been associated with diseases like cancer, regulate mRNA stability, subcellular localization, and translation. By characterizing APA across the 24-hour day in mouse liver, here we show that rhythmic gene expression occurs largely in an APA isoform-specific manner, and that hundreds of arrhythmically expressed genes surprisingly exhibit a rhythmic APA isoform. The underlying mechanisms comprise isoform-specific post-transcriptional regulation, transcription factor driven expression of specific isoform, co-transcriptional recruitment of RNA binding proteins that regulate mRNA cleavage and polyadenylation, and, to a lesser extent, cell subtype-specific expression. Remarkably, rhythmic expression of specific APA isoforms generates 24-hour rhythms in 3’ UTR length, with shorter UTRs in anticipation of the mouse active phase. Taken together, our findings demonstrate that cycling transcriptomes are regulated by APA, and suggest that APA strongly impacts the rhythmic regulation of biological functions.