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Zinc finger homeobox-3 (ZFHX3) exerts genome-wide regulation of dailygene expression in the suprachiasmatic nucleus [RNA-seq]

ABSTRACT: The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological 24-hr rhythms across the body. The cell-autonomous timing mechanism is based on a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn co-ordinates the expression of clock-controlled genes (CCGs) that direct 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 transcriptome and genome levels are, however, poorly defined. Here, we used chromatin immunoprecipitation (ChIP-seq) to map the genomic localization of ZFHX3 sites in the SCN. In parallel, we conducted a comprehensive SCN RNA sequencing at six distinct times-of-day, and then compared the transcriptional profile between the control and ZFHX3-conditional null mutants. We show that the genome wide occupancy of ZFHX3 occurs predominantly around the gene transcription start site (TSS), co-localizing with the known histone modifications, and preferentially partnering with the core-clock TFs (CLOCK, BMAL1) to regulate the clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, reducing the level of neuropeptides-encoding transcripts and abolishing rhythmic (24-h) oscillation of the clock TF, Bmal1. In addition, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with the advanced daily behaviour under 12hr light- 12hr dark conditions. Taken together, these findings reveal the extensive genome-wide regulation conferred by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE261429 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description:To screen for specific circadian outputs that may distinguish the pacemaker in the mammalian suprachiasmatic nucleus (SCN) from peripheral-type oscillators in which the canonical clockworks are similarly regulated in a circadian manner, the rhythmic behavior of the transcriptome in forskolin-stimulated NIH/3T3 fibroblasts was analyzed and compared to that found in the rat SCN in vivo and SCN2.2 cells in vitro. Similar to the scope of circadian gene expression in SCN2.2 cells and the rat SCN, NIH/3T3 fibroblasts exhibited circadian fluctuations in the expression of the core clock genes, Per2, Bmal1 (Mop3), and Cry1 and 323 functionally diverse transcripts (2.6%), many of which were involved in cell communication. Overlap in rhythmically-expressed transcripts among NIH/3T3 fibroblasts, SCN2.2 cells and the rat SCN was limited to these clock genes and four other genes that mediate fatty acid and lipid metabolism or function as nuclear factors. Compared to NIH/3T3 cells, circadian gene expression in SCN oscillators was more prevalent among cellular pathways mediating glucose metabolism and neurotransmission. Coupled with evidence for the rhythmic regulation of the inducible isoform of nitric oxide synthase, the enzyme responsible for the production of nitric oxide, in SCN2.2 cells and the rat SCN but not in fibroblasts, studies examining the effects of a NOS inhibitor on metabolic rhythms in co-cultures containing SCN2.2 cells and untreated NIH/3T3 cells suggest that this gaseous neurotransmitter may play a key role in SCN pacemaker function. Thus, this comparative analysis of circadian gene expression in SCN and non-SCN cells may have important implications in the selective identification of circadian signals involved in the coupling of SCN oscillators and the regulation of rhythmicity in downstream cells or tissues. Experiment Overall Design: Circadian profiling of the NIH/3T3 fibroblast transcriptome entailed the treatment of NIH/3T3 cells with a 15uM forskolin pulse, subsequent washout of the drug, and collection of total RNA immediately after washout and every 6 hours across two circadian cycles for each of three experiments. Timepoint values reflect the average of three samples from these biological replicates.

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Zinc finger homeobox-3 (ZFHX3) exerts genome-wide regulation of dailygene expression in the suprachiasmatic nucleus [RNA-seq]

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