Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus

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Bafna, A, Banks, G ORCID: https://orcid.org/0000-0002-8647-667X, Vasilyev, V, Dallmann, R, Hastings, MH and Nolan, PM, 2025. Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus. eLife. ISSN 2050-084X (Forthcoming)

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Official URL: https://doi.org/10.7554/elife.102019.1

Abstract

The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn co-ordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing (ChIP-seq) to map the genomic localization of ZFHX3 binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites (TSS), co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12h light-12h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.

Item Type:	Journal article
Publication Title:	eLife
Creators:	Bafna, A., Banks, G., Vasilyev, V., Dallmann, R., Hastings, M.H. and Nolan, P.M.
Publisher:	eLife Sciences Publications
Date:	22 January 2025
ISSN:	2050-084X
Identifiers:	Number Type 10.7554/elife.102019.1 DOI 2356161 Other
Rights:	This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	03 Feb 2025 09:06
Last Modified:	03 Feb 2025 09:06
URI:	https://irep.ntu.ac.uk/id/eprint/52952