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

Michael Parsons | Zendy; Marco Brancaccio | Zendy; Siddharth Sethi | Zendy; Elizabeth S. Maywood | Zendy; Rahul Satija | Zendy; Jessica K. Edwards | Zendy; Aarti Jagannath | Zendy; Yvonne Couch | Zendy; Mattéa J. Finelli | Zendy; Nicola J. Smyllie | Zendy; Christopher T. Esapa | Zendy; Rachel Butler | Zendy; Alun R. Barnard | Zendy; Johanna E. Chesham | Zendy; Shoko Saito | Zendy; Greg Joynson | Zendy; Sara Wells | Zendy; F. Foster | Zendy; Peter L. Oliver | Zendy; Michelle M. Simon | Zendy; AnnMarie Mallon | Zendy; Michael H. Hastings | Zendy; Patrick M. Nolan | Zendy

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

Author(s) -

Michael Parsons,

Marco Brancaccio,

Siddharth Sethi,

Elizabeth S. Maywood,

Rahul Satija,

Jessica K. Edwards,

Aarti Jagannath,

Yvonne Couch,

Mattéa J. Finelli,

Nicola J. Smyllie,

Christopher T. Esapa,

Rachel Butler,

Alun R. Barnard,

Johanna E. Chesham,

Shoko Saito,

Greg Joynson,

Sara Wells,

F. Foster,

Peter L. Oliver,

Michelle M. Simon,

AnnMarie Mallon,

Michael H. Hastings,

Patrick M. Nolan

Publication year - 2015

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2015.06.060

Subject(s) - biology , circadian rhythm , transcription factor , motif (music) , microbiology and biotechnology , computational biology , genetics , endocrinology , gene , physics , acoustics

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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