@article{ff0a5646858d4288ae5d6136cbdad05e,
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 (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.}",
note = "Funding Information: P.M.N. and M.H.H. were supported by the MRC and by the 6th Framework Project EUCLOCK (No. 018741). R.S. was supported by an MRC Biomedical Informatics Fellowship. P.L.O. and M.J.F. were supported by a European Research Council Starting Grant “PAROSIN” awarded to P.L.O. A.J. was supported by a WT grant (090684/Z/09/Z). We thank Dr. Takahashi for generously providing the PER2::LUC knockin mice. We thank Dr. Filippo Tamanini for the CLOCK and BMAL expression vectors. We thank Dr. J{\"u}rgen Ripperger for generously providing the DBP expression vector. We thank the biomedical staff at the Mary Lyon Center, MRC Harwell, and the Ares Facility, Cambridge. Thanks to Steve Thomas for reformatting the figure images, and thanks to Helen Hilton for work validating the anti-ZFHX3 antibody. ",
year = "2015",
month = aug,
day = "1",
doi = "10.1016/j.cell.2015.06.060",
language = "English (US)",
volume = "162",
pages = "607--621",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}