Abstract
A substantial fraction of the metazoan transcriptome undergoes circadian oscillations in many cells and tissues. Based on the transcription feedback loops important for circadian timekeeping, it is commonly assumed that this mRNA cycling reflects widespread transcriptional regulation. To address this issue, we directly measured the circadian dynamics of mouse liver transcription using Nascent-Seq (genome-wide sequencing of nascent RNA). Although many genes are rhythmically transcribed, many rhythmic mRNAs manifest poor transcriptional rhythms, indicating a prominent contribution of post-transcriptional regulation to circadian mRNA expression. This analysis of rhythmic transcription also showed that the rhythmic DNA binding profile of the transcription factors CLOCK and BMAL1 does not determine the transcriptional phase of most target genes. This likely reflects gene-specific collaborations of CLK:BMAL1 with other transcription factors. These insights from Nascent-Seq indicate that it should have broad applicability to many other gene expression regulatory issues.DOI:http://dx.doi.org/10.7554/eLife.00011.001.
Highlights
Most organisms from bacteria to humans possess circadian rhythms, which generate oscillations in biochemistry, physiology and behavior
To address the regulation of genome-wide transcription, we analyzed mouse liver nascent RNA expression, that is, RNA being transcribed by RNA Polymerase II (Pol II) prior to 3′ end formation
Nascent-Seq signals frequently extend past the polyadenylation site, reflecting RNA not yet cleaved by the cleavage/polyadenylation specificity factor (CPSF) and/or RNA molecules still associated with Pol II after cleavage but prior to degradation by the 5′ to 3′ exoribonuclease Xrn2 (Figure 1C)
Summary
Most organisms from bacteria to humans possess circadian rhythms, which generate oscillations in biochemistry, physiology and behavior. The PERs and CRYs are expressed, post-translationally modified, feedback to inhibit their own transcription and are rhythmically degraded to lead to a new round of BMAL1:CLK or BMAL1:NPAS2 -mediated transcription (reviewed in Ko and Takahashi, 2006; Dardente and Cermakian, 2007). This temporal regulation of clock gene transcription cycles with a period of about 24 hr and probably underlies much of circadian biology.
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