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The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.

Authors:
Michael J Parsons Marco Brancaccio Siddharth Sethi Elizabeth S Maywood Rahul Satija Jessica K Edwards Aarti Jagannath Yvonne Couch Mattéa J Finelli Nicola J Smyllie Christopher Esapa Rachel Butler Alun R Barnard Johanna E Chesham Shoko Saito Greg Joynson Sara Wells Russell G Foster Peter L Oliver Michelle M Simon Ann-Marie Mallon Michael H Hastings Patrick M Nolan

Cell 2015 Jul;162(3):607-21

MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK. Electronic address:

We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3(Sci)), 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 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. In conclusion, by cloning Zfhx3(Sci), we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

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http://dx.doi.org/10.1016/j.cell.2015.06.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537516PMC
July 2015

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