title: The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.
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.
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parsons
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Brancaccio
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sethi
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Maywood
authors.affiliation: New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10012, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Satija
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Edwards
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Aarti
authors.initials: A
authors.lastname: Jagannath
authors.affiliation: Acute Stroke Program, Radcliffe Department of Clinical Medicine, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Couch
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Mattéa J
authors.initials: MJ
authors.lastname: Finelli
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Smyllie
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Esapa
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Butler
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Alun R
authors.initials: AR
authors.lastname: Barnard
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Chesham
authors.affiliation: Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands; Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Saito
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Greg
authors.initials: G
authors.lastname: Joynson
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Foster
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Simon
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Mallon
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hastings
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK. Electronic address: p.nolan@har.mrc.ac.uk.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002940:Circadian Rhythm; D015536:Down-Regulation; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics*; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D009479:Neuropeptides; C489511:Zfhx3 protein, mouse