The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.
Bottom Line: Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3(Sci/+) 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 Zfhx3(Sci/+) SCN slices.
Affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.Show MeSH
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Mentions: It is clear from our results that the period of AT-driven transcription is sensitive to the period of the TTFL, as evidenced by the effect of CK1 inhibition. This argues that the ZFHX3/AT axis is downstream of the TTFL. However, it is also affected by the Zfhx3Sci mutation, as is the period of the TTFL, as reported by PER expression. The TTFL and AT axes are, therefore, reciprocally dependent, each able to influence the other. We propose that this arises from the circuit-level effects of AT-driven transcription, specifically of neuropeptide-encoding genes, leading to a logical module in which the TTFL affects AT function. In turn, AT motif activation affects neuropeptidergic expression, leading to cell-nonautonomous effects on circuit-level signaling in the SCN, and ultimately influences TTFL activity (Figure 7).
Affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.