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

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. SimonAnn Marie Mallon, Michael H. Hastings, Patrick M. Nolan

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)607-621
Number of pages15
JournalCell
Volume162
Issue number3
DOIs
StatePublished - Aug 1 2015

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Short circuit currents
Neuropeptides
Genes
RNA Sequence Analysis
Missense Mutation
Mutant Proteins
Circadian Rhythm
Organism Cloning
Cloning
Transcription Factors
Transcription
Clocks
Chemical activation
RNA
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Parsons, M. J., Brancaccio, M., Sethi, S., Maywood, E. S., Satija, R., Edwards, J. K., ... Nolan, P. M. (2015). The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an at Motif-Driven Axis. Cell, 162(3), 607-621. https://doi.org/10.1016/j.cell.2015.06.060

The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an at Motif-Driven Axis. / Parsons, Michael J.; Brancaccio, Marco; Sethi, Siddharth; Maywood, Elizabeth S.; Satija, Rahul; Edwards, Jessica K.; Jagannath, Aarti; Couch, Yvonne; Finelli, Mattéa J.; Smyllie, Nicola J.; Esapa, Christopher; Butler, Rachel; Barnard, Alun R.; Chesham, Johanna E.; Saito, Shoko; Joynson, Greg; Wells, Sara; Foster, Russell G.; Oliver, Peter L.; Simon, Michelle M.; Mallon, Ann Marie; Hastings, Michael H.; Nolan, Patrick M.

In: Cell, Vol. 162, No. 3, 01.08.2015, p. 607-621.

Research output: Contribution to journalArticle

Parsons, MJ, Brancaccio, M, Sethi, S, Maywood, ES, Satija, R, Edwards, JK, Jagannath, A, Couch, Y, Finelli, MJ, Smyllie, NJ, Esapa, C, Butler, R, Barnard, AR, Chesham, JE, Saito, S, Joynson, G, Wells, S, Foster, RG, Oliver, PL, Simon, MM, Mallon, AM, Hastings, MH & Nolan, PM 2015, 'The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an at Motif-Driven Axis', Cell, vol. 162, no. 3, pp. 607-621. https://doi.org/10.1016/j.cell.2015.06.060
Parsons, Michael J. ; Brancaccio, Marco ; Sethi, Siddharth ; Maywood, Elizabeth S. ; Satija, Rahul ; Edwards, Jessica K. ; Jagannath, Aarti ; Couch, Yvonne ; Finelli, Mattéa J. ; Smyllie, Nicola J. ; Esapa, Christopher ; Butler, Rachel ; Barnard, Alun R. ; Chesham, Johanna E. ; Saito, Shoko ; Joynson, Greg ; Wells, Sara ; Foster, Russell G. ; Oliver, Peter L. ; Simon, Michelle M. ; Mallon, Ann Marie ; Hastings, Michael H. ; Nolan, Patrick M. / The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an at Motif-Driven Axis. In: Cell. 2015 ; Vol. 162, No. 3. pp. 607-621.
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AU - Maywood, Elizabeth S.

AU - Satija, Rahul

AU - Edwards, Jessica K.

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AU - Joynson, Greg

AU - Wells, Sara

AU - Foster, Russell G.

AU - Oliver, Peter L.

AU - Simon, Michelle M.

AU - Mallon, Ann Marie

AU - Hastings, Michael H.

AU - Nolan, Patrick M.

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