Abstract
SummaryWe identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), which accelerates circadian locomotor rhythms in mice. ZFHX3 regulates transcription via direct interaction with predicted AT motifs in target genes. The mutant protein has a decreased ability to activate consensus AT motifs in vitro. Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3Sci/+ SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed. Moreover, mutant ZFHX3 had a decreased ability to activate AT motifs in the promoters of these neuropeptide genes. Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.
Highlights
Circadian rhythms are daily cycles with periods of 24 hr that affect multiple distinct physiological and behavioral outputs
We found a significant increase in immunoprecipitated DNA upstream of the transcriptional start site (TSS) for both arginine vasopressin (Avp) and Vip compared to the Gapdh control promoter region, suggesting that ZFHX3 binds to both target gene promoters (Figures 6A and 6B)
We show that activation of AT-dependent transcription follows a clear circadian cycle in the suprachiasmatic nucleus (SCN), that the rhythm is sensitive to ZFHX3 function, and that it may be downstream of the core translational feedback loop (TTFL)
Summary
Circadian rhythms are daily cycles with periods of 24 hr that affect multiple distinct physiological and behavioral outputs. The current canonical model of the core molecular clock consists of a well-characterized transcriptional-translational feedback loop (TTFL), where CLOCK and BMAL1 drive the expression of E-box-regulated genes, including Per and Cry, whose protein products, in turn, negatively regulate these same genes by interacting with the CLOCK:BMAL1 complex (Zhang and Kay, 2010). Most cells contain such molecular clocks (Albrecht, 2012) synchronized to each other and to the external environment by signals derived from the principal circadian pacemaker, the suprachiasmatic nucleus (SCN) (Ralph et al, 1990). These and additional peptides, including neuromedin S (NMS) and prokineticin 2 (PROK2), A
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