Abstract:Circadian clocks maintain whole-body metabolic homeostasis by coordinating rhythmic gene expression in multiple tissues. Core clock regulators sustain their own oscillation and confer expression rhythmicity on clock-controlled genes (CCGs). Our unbiased examination of enhancer RNA (eRNA) transcription around the clock in mouse liver identified functional enhancers of circadian genes driven by phase-specific transcription factors (TFs). Rev-erba emerged as a primary driver of circadian enhancers, leading to osc… Show more
“…It is hence conceivable that adjusting the relative levels of NR1D1/2 versus RORs tailors clock-controlled gene expression in a tissue-specific fashion. Our observation of an active state of this output branch in liver and a more repressed state in kidney is fully consistent with the current knowledge of its target genes and knockout phenotypes, which point to a prominent role in the regulation of hepatic pathways such as lipid, cholesterol and bile acid metabolism [26]. Fig.…”
BackgroundThe daily gene expression oscillations that underlie mammalian circadian rhythms show striking differences between tissues and involve post-transcriptional regulation. Both aspects remain poorly understood. We have used ribosome profiling to explore the contribution of translation efficiency to temporal gene expression in kidney and contrasted our findings with liver data available from the same mice.ResultsRhythmic translation of constantly abundant messenger RNAs (mRNAs) affects largely non-overlapping transcript sets with distinct phase clustering in the two organs. Moreover, tissue differences in translation efficiency modulate the timing and amount of protein biosynthesis from rhythmic mRNAs, consistent with organ specificity in clock output gene repertoires and rhythmicity parameters. Our comprehensive datasets provided insights into translational control beyond temporal regulation. Between tissues, many transcripts show differences in translation efficiency, which are, however, of markedly smaller scale than mRNA abundance differences. Tissue-specific changes in translation efficiency are associated with specific transcript features and, intriguingly, globally counteracted and compensated transcript abundance variations, leading to higher similarity at the level of protein biosynthesis between both tissues.ConclusionsWe show that tissue specificity in rhythmic gene expression extends to the translatome and contributes to define the identities, the phases and the expression levels of rhythmic protein biosynthesis. Moreover, translational compensation of transcript abundance divergence leads to overall higher similarity at the level of protein production across organs. The unique resources provided through our study will serve to address fundamental questions of post-transcriptional control and differential gene expression in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1222-2) contains supplementary material, which is available to authorized users.
“…It is hence conceivable that adjusting the relative levels of NR1D1/2 versus RORs tailors clock-controlled gene expression in a tissue-specific fashion. Our observation of an active state of this output branch in liver and a more repressed state in kidney is fully consistent with the current knowledge of its target genes and knockout phenotypes, which point to a prominent role in the regulation of hepatic pathways such as lipid, cholesterol and bile acid metabolism [26]. Fig.…”
BackgroundThe daily gene expression oscillations that underlie mammalian circadian rhythms show striking differences between tissues and involve post-transcriptional regulation. Both aspects remain poorly understood. We have used ribosome profiling to explore the contribution of translation efficiency to temporal gene expression in kidney and contrasted our findings with liver data available from the same mice.ResultsRhythmic translation of constantly abundant messenger RNAs (mRNAs) affects largely non-overlapping transcript sets with distinct phase clustering in the two organs. Moreover, tissue differences in translation efficiency modulate the timing and amount of protein biosynthesis from rhythmic mRNAs, consistent with organ specificity in clock output gene repertoires and rhythmicity parameters. Our comprehensive datasets provided insights into translational control beyond temporal regulation. Between tissues, many transcripts show differences in translation efficiency, which are, however, of markedly smaller scale than mRNA abundance differences. Tissue-specific changes in translation efficiency are associated with specific transcript features and, intriguingly, globally counteracted and compensated transcript abundance variations, leading to higher similarity at the level of protein biosynthesis between both tissues.ConclusionsWe show that tissue specificity in rhythmic gene expression extends to the translatome and contributes to define the identities, the phases and the expression levels of rhythmic protein biosynthesis. Moreover, translational compensation of transcript abundance divergence leads to overall higher similarity at the level of protein production across organs. The unique resources provided through our study will serve to address fundamental questions of post-transcriptional control and differential gene expression in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1222-2) contains supplementary material, which is available to authorized users.
“…Circadian enhancers phasing in ZT9‐ZT12 were found to be enriched for this D‐box motif, while REV‐DR2/ROR motifs were found enriched in regulatory sequences of a distinct set of CCGs that peak around ZT18‐ZT24 27. The rhythmic binding of these respective binding factors (BMAL1/CLOCK, E4BP4, REV‐ERB/ROR) hints toward a molecular mechanism in which phase‐specific oscillators rhythmically influence circadian enhancers 27, 28.…”
Section: Establishment Of the Clock Through Tissue‐specific Transcripmentioning
The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep‐to‐wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and CLOCK on clock‐controlled output genes, which results in tissue‐specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging.
“…The circadian transcriptional regulator Rev-erbα uses heme as ligand and functions as a transcriptional repressor by forming a complex with the co-repressor, NCoR and HDAC3 (reviewed in Fang and Lazar 2015). As a feedback mechanism, Rev-erbα controls its own activity by modulating the levels of heme via repression of PGC-1α, which activates the expression of delta-aminolevulinate synthase-1 (ALAS-1), the rate-limiting enzyme in the biosynthesis of heme (Zheng et al, 2008; Estall et al, 2009) (Figure 5).…”
Section: Circadian Rhythms Linked To Chromatin Metabolism and Diseasementioning
The physiological identity of every cell is maintained by highly specific transcriptional networks that establish a coherent molecular program that is in-tune with nutritional conditions. The regulation of cell-specific transcriptional networks is accomplished by an epigenetic program via chromatin modifying enzymes, whose activity is directly dependent on metabolites such as acetyl-CoA, S-adenosylmethionine and NAD+ among others. Therefore, these nuclear activities are directly influenced by the nutritional status of the cell. In addition to nutritional availability, this highly collaborative program between epigenetic dynamics and metabolism is further interconnected with other environmental cues provided by the day-night cycles imposed by circadian rhythms. Herein, we review molecular pathways and their metabolites associated with epigenetic adaptations modulated by histone- and DNA-modifying enzymes and their responsiveness to the environment in the context of health and disease.
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