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. Simon; Ann Marie Mallon; Michael H. Hastings; Patrick M. Nolan

doi:10.1016/j.cell.2015.06.060

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

Biology and Genomics

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	607-621
Number of pages	15
Journal	Cell
Volume	162
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2015.06.060
State	Published - Aug 1 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Parsons, M. J., Brancaccio, M., Sethi, S., Maywood, E. S., Satija, R., Edwards, J. K., Jagannath, A., Couch, Y., Finelli, M. J., Smyllie, N. J., Esapa, C., Butler, R., Barnard, A. R., Chesham, J. E., Saito, S., Joynson, G., Wells, S., Foster, R. G., Oliver, P. L., ... 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 journal › Article › peer-review

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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abstract = "We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), 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 Zfhx3Sci/+ 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 Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.",

author = "Parsons, {Michael J.} and Marco Brancaccio and Siddharth Sethi and Maywood, {Elizabeth S.} and Rahul Satija and Edwards, {Jessica K.} and Aarti Jagannath and Yvonne Couch and Finelli, {Matt{\'e}a J.} and Smyllie, {Nicola J.} and Christopher Esapa and Rachel Butler and Barnard, {Alun R.} and Chesham, {Johanna E.} and Shoko Saito and Greg Joynson and Sara Wells and Foster, {Russell G.} and Oliver, {Peter L.} and Simon, {Michelle M.} and Mallon, {Ann Marie} and Hastings, {Michael H.} and Nolan, {Patrick M.}",

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AU - Parsons, Michael J.

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AU - Sethi, Siddharth

AU - Maywood, Elizabeth S.

AU - Satija, Rahul

AU - Edwards, Jessica K.

AU - Jagannath, Aarti

AU - Couch, Yvonne

AU - Finelli, Mattéa J.

AU - Smyllie, Nicola J.

AU - Esapa, Christopher

AU - Butler, Rachel

AU - Barnard, Alun R.

AU - Chesham, Johanna E.

AU - Saito, Shoko

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.

PY - 2015/8/1

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N2 - We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), 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 Zfhx3Sci/+ 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 Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

AB - We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), 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 Zfhx3Sci/+ 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 Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

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