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

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From: Cell(Vol. 162, Issue 3)
Publisher: Elsevier B.V.
Document Type: Article
Length: 463 words

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To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: Byline: Michael J. Parsons (1), Marco Brancaccio (2), Siddharth Sethi (1), Elizabeth S. Maywood (2), Rahul Satija (3,4), Jessica K. Edwards (1), Aarti Jagannath (5), Yvonne Couch (6), MattAaAaAeA@a J. Finelli (7 Nicola J. Smyllie (2), Christopher Esapa (1), Rachel Butler (5), Alun R. Barnard (5), Johanna E. Chesham (2), Shoko Saito (8,9), Greg Joynson (1), Sara Wells (1), Russell G. Foster (5), Peter L. Oliver (7), Michelle M. Simon (1), Ann-Marie Mallon (1), Michael H. Hastings (2), Patrick M. Nolan [] (1,*) Highlights * Zfhx3 missense mutation underlies the short circuit (Zfhx3.sup.Sci) circadian phenotype * Zfhx3.sup.Sci reduces the ability of ZFHX3 to activate transcription via AT motifs * Zfhx3.sup.Sci phenotype is associated with decreased activation of AT motif in neuropeptide promoters * Circadian activation in SCN reveals AT motif as a new clock-regulated transcriptional axis Summary We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3.sup.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.sup.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.sup.Sci/+ SCN slices. In conclusion, by cloning Zfhx3.sup.Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms. Author Affiliation: (1) MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK (2) MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK (3) New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA (4) Department of Biology, New York University, New York, NY 10012, USA (5) Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK (6) Acute Stroke Program, Radcliffe Department of Clinical Medicine, University of Oxford, Oxford OX3 9DU, UK (7) MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK (8) Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands (9) Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan * Corresponding author Article History: Received 15 October 2014; Revised 25 March 2015; Accepted 1 June 2015 (miscellaneous) Published: July 30, 2015 (footnote) This is an open access article under the CC BY license (

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Gale Document Number: GALE|A517683016