Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus
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 coordinates the expression of clock-controlled g...
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eLife Sciences Publications Ltd
2025-03-01
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| Online Access: | https://elifesciences.org/articles/102019 |
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| author | Akanksha Bafna Gareth Banks Vadim Vasilyev Robert Dallmann Michael H Hastings Patrick M Nolan |
| author_facet | Akanksha Bafna Gareth Banks Vadim Vasilyev Robert Dallmann Michael H Hastings Patrick M Nolan |
| author_sort | Akanksha Bafna |
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| description | 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 coordinates 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 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, 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 12 h light–12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-2ad814ff573f41108bd75d8104e4e3202025-08-20T03:41:53ZengeLife Sciences Publications LtdeLife2050-084X2025-03-011410.7554/eLife.102019Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleusAkanksha Bafna0https://orcid.org/0000-0002-6666-5318Gareth Banks1Vadim Vasilyev2Robert Dallmann3https://orcid.org/0000-0002-7490-0218Michael H Hastings4https://orcid.org/0000-0001-8576-6651Patrick M Nolan5Medical Research Council, Harwell Science Campus, Didcot, United Kingdom; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxfordshire, United KingdomMedical Research Council, Harwell Science Campus, Didcot, United Kingdom; Nottingham Trent University, Nottingham, United KingdomDivision of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United KingdomDivision of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom; Zeeman Institute for Systems Biology and Infectious Disease Epidemiology Research, University of Warwick, Coventry, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMedical Research Council, Harwell Science Campus, Didcot, United KingdomThe 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 coordinates 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 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, 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 12 h light–12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.https://elifesciences.org/articles/102019circadian rhythmgenomicsSCN |
| spellingShingle | Akanksha Bafna Gareth Banks Vadim Vasilyev Robert Dallmann Michael H Hastings Patrick M Nolan Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus eLife circadian rhythm genomics SCN |
| title | Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus |
| title_full | Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus |
| title_fullStr | Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus |
| title_full_unstemmed | Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus |
| title_short | Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus |
| title_sort | zinc finger homeobox 3 zfhx3 orchestrates genome wide daily gene expression in the suprachiasmatic nucleus |
| topic | circadian rhythm genomics SCN |
| url | https://elifesciences.org/articles/102019 |
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