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Clockwork orange-mediated control of sugar responsive transcription [ChIP-seq]

ABSTRACT: Feeding on high sugar diet reprograms metabolism, partially mediated through a gene regulatory network controlled by intracellular sugar sensor Mondo/ChREBP-Mlx. Sugar-induced gene expression changes include activation of genes encoding enzymes of glycolysis, pentose phosphate pathways, and de novo lipogenesis, collectively driving the flux of sugar-derived carbon into triacylglycerides. These sugar-induced metabolic changes are likely to trigger compensatory responses to avoid depletion of necessary metabolites, but they remain poorly characterized. Through a global temporal clustering analysis of sugar-induced gene expression in Drosophila we identify new gene expression programs controlled by sugar feeding. These include rapid and transient downregulation of ribosome biogenesis genes, known targets of transcription factor Myc. Through in silico motif predictions and experimental validation, we identify transcriptional repressor Clockwork orange (CWO) as a mediator of this response. CWO expression is directly activated by Mondo-Mlx and it counteracts Myc through repression of its expression as well as through binding to overlapping regulatory regions of ribosome biogenesis genes. Loss of CWO function leads to depletion of UDP-GlcNAc pools and impaired viability on high sugar diet. Analysis of CWO orthologs, BHLHE40 and BHLHE41, in mouse hepatocytes revealed a conserved role for BHLHE41 in repressing ribosome biogenesis genes. Collectively, our data uncover a gene regulatory circuit balancing the activities of lipid and protein biosynthesis to maintain homeostasis during high sugar feeding.

ORGANISM(S): Mus musculus

PROVIDER: GSE207198 | GEO | 2023/06/01

REPOSITORIES: GEO

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Clockwork orange-mediated control of sugar responsive transcription [time series]

Project description:Feeding on high sugar diet reprograms metabolism, partially mediated through a gene regulatory network controlled by intracellular sugar sensor Mondo/ChREBP-Mlx. Sugar-induced gene expression changes include activation of genes encoding enzymes of glycolysis, pentose phosphate pathways, and de novo lipogenesis, collectively driving the flux of sugar-derived carbon into triacylglycerides. These sugar-induced metabolic changes are likely to trigger compensatory responses to avoid depletion of necessary metabolites, but they remain poorly characterized. Through a global temporal clustering analysis of sugar-induced gene expression in Drosophila we identify new gene expression programs controlled by sugar feeding. These include rapid and transient downregulation of ribosome biogenesis genes, known targets of transcription factor Myc. Through in silico motif predictions and experimental validation, we identify transcriptional repressor Clockwork orange (CWO) as a mediator of this response. CWO expression is directly activated by Mondo-Mlx and it counteracts Myc through repression of its expression as well as through binding to overlapping regulatory regions of ribosome biogenesis genes. Loss of CWO function leads to depletion of UDP-GlcNAc pools and impaired viability on high sugar diet. Analysis of CWO orthologs, BHLHE40 and BHLHE41, in mouse hepatocytes revealed a conserved role for BHLHE41 in repressing ribosome biogenesis genes. Collectively, our data uncover a gene regulatory circuit balancing the activities of lipid and protein biosynthesis to maintain homeostasis during high sugar feeding.

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Clockwork orange-mediated control of sugar responsive transcription [cwo mutant]

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Sugar responsive regulatory network that controls organismal carbohydrate, amino acid and lipid homeostasis [set 2]

Project description:Maintaining metabolic homeostasis in response to fluctuating nutrient intake requires intricate coordination between tissues of multicellular animals. The insulin/glucagon axis is well known to hormonally coordinate organism-wide carbohydrate metabolism. The ChREBP/Mondo-Mlx transcription factors regulate glycolytic and lipogenic genes locally in hepatocytes and adipocytes, but its role in systemic metabolic homeostasis has remained poorly understood. We demonstrate that Mondo-Mlx controls gene activity in several peripheral tissues of Drosophila melanogaster, where it regulates nutrient digestion and transport as well as carbohydrate, amino acid and lipid metabolism. In addition to directly regulating metabolic genes Mondo-Mlx controls a regulatory network composed of the Activin ligand Dawdle and GLI similar transcription factor Sugarbabe. Dawdle and Sugarbabe contribute to the regulation of a subset of Mondo-Mlx-dependent processes, including sugar-induced de novo synthesis of serine and fatty acids. In summary, our study establishes Mondo-Mlx sugar sensor as a master regulator of organismal metabolic homeostasis upon sugar feeding.

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Small molecule RBI2 disrupts ribosome biogenesis through pre-rRNA depletion

Project description:In all domains of life, the rate of protein synthesis is directly linked to the rates of cell growth and proliferation. Consequently, highly proliferative cancer cells are especially sensitive to perturbations in ribosome biogenesis. While ribosome synthesis and cancer have a well-established relationship, only recently has ribosome biogenesis drawn interest as a cancer therapeutic target. Here, we have exploited the relationship between ribosome biogenesis and cancer cell proliferation by using a potent ribosome biogenesis inhibitor: RBI2 (Ribosome Biogenesis Inhibitor 2) to perturb cancer cell growth and viability. We demonstrate that RBI2 significantly decreases cell viability in malignant melanoma cells and breast cancer cell lines. Treatment with RBI2 dramatically and rapidly decreases ribosomal RNA (rRNA) synthesis, without affecting the occupancy of RNA polymerase I (Pol I) on the ribosomal DNA template. Next-generation RNA sequencing (RNA-seq) reveals that RBI2 and previously described ribosome biogenesis inhibitor CX-5461 induce distinct changes in the transcriptome. Investigation of the content of the pre-rRNAs through RT-qPCR reveals an increase in polyadenylation of cellular rRNA after treatment with RBI2, a known pathway by which rRNA degradation occurs. Northern blotting revealed that RBI2 does not appear to impair or alter rRNA processing. Collectively, these data suggest that RBI2 inhibits rRNA synthesis distinctly from other previously described ribosome biogenesis inhibitors, potentially through a novel pathway that upregulates turnover of premature rRNAs.

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CLOCKWORK ORANGE promotes CLOCK-CYCLE activation via the Drosophila ortholog of CLOCK INTERACING PROTEIN, CIRCADIAN (RNA-Seq)

Project description:The Drosophila circadian clock is driven by a transcriptional feedback loop in which the bHLH transcription factor CLOCK-CYCLE (CLK-CYC) binds E-boxes to transcribe genes encoding the PERIOD-TIMELESS (PER-TIM) repressor, which releases CLK-CYC from E-boxes to inhibit transcription. The bHLH-Orange transcription factor CLOCKWORK ORANGE (CWO) reinforces repression by binding E-boxes to displace CLK-CYC, but also acts through an unknown mechanism to promote CLK-CYC transcription. To determine how CWO activates CLK-CYC transcription, we identified CWO DNA binding targets that are upregulated in the absence of CWO repression, conserved in mammals and preferentially expressed in brain pacemaker neurons. Among the genes identified was the Drosophila ortholog of mammalian Clock Interacting Protein Circadian (Cipc) that acts to repress CLOCK-BMAL1 transcription. Reducing or eliminating Drosophila Cipc expression shortens circadian period while overexpressing Cipc lengthens circadian period in flies, consistent with previous analysis showing that Drosophila Cipc represses CLK-CYC transcription in S2 cell culture. Long period rhythms of cwo mutant flies are largely rescued when Cipc expression is reduced or eliminated, indicating that increased Cipc expression mediates period lengthening of cwo mutants. These results suggest a mechanism for CWO-dependent CLK-CYC activation: CWO inhibition of CIPC repression promotes CLK-CYC transcription. Such a mechanism may be conserved given that orthologs of cwo and Cipc carry out analogous roles in the mammalian circadian clock.

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