Modulation of the Promoter Activation Rate Dictates the Transcriptional Response to Graded BMP Signaling Levels in the Drosophila Embryo.
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ABSTRACT:
SUBMITTER: Hoppe C
PROVIDER: S-EPMC7527239 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Transcriptional repressors are thought to inhibit gene expression by interfering with the binding or function of RNA Polymerase II, perhaps by promoting local chromatin condensation. Here, we present evidence for a distinctive mechanism of repression, whereby sequence-specific repressors prevent the looping of distal enhancers to the promoter. Particular efforts focus on the Snail repressor, which plays a conserved role in promoting epithelial-mesenchyme transitions in both invertebrates and vertebrates, including mesoderm invagination in Drosophila, neural crest migration in vertebrates, and tumorigenesis in mammals. Chromosome conformation capture experiments were used to examine enhancer looping at Snail target genes in wild-type and mutant embryos. These studies suggest that the Snail repressor blocks the formation of fruitful enhancer-promoter interactions when bound to a distal enhancer. This higher-order mechanism of transcriptional repression has broad implications for the control of gene activity in metazoan development.
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Project description:Study Objectives:Dysregulation of sleep is associated with metabolic diseases, and metabolic rate (MR) is acutely regulated by sleep-wake behavior. In humans and rodent models, sleep loss is associated with obesity, reduced metabolic rate, and negative energy balance, yet little is known about the neural mechanisms governing interactions between sleep and metabolism. Methods:We have developed a system to simultaneously measure sleep and MR in individual Drosophila, allowing for interrogation of neural systems governing interactions between sleep and metabolic rate. Results:Like mammals, MR in flies is reduced during sleep and increased during sleep deprivation suggesting sleep-dependent regulation of MR is conserved across phyla. The reduction of MR during sleep is not simply a consequence of inactivity because MR is reduced ~30 minutes following the onset of sleep, raising the possibility that CO2 production provides a metric to distinguish different sleep states in the fruit fly. To examine the relationship between sleep and metabolism, we determined basal and sleep-dependent changes in MR is reduced in starved flies, suggesting that starvation inhibits normal sleep-associated effects on metabolic rate. Further, translin mutant flies that fail to suppress sleep during starvation demonstrate a lower basal metabolic rate, but this rate was further reduced in response to starvation, revealing that regulation of starvation-induced changes in MR and sleep duration are genetically distinct. Conclusions:Therefore, this system provides the unique ability to simultaneously measure sleep and oxidative metabolism, providing novel insight into the physiological changes associated with sleep and wakefulness in the fruit fly.
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Project description:Within a 3D tissue, cells need to integrate signals from growth factors, such as BMPs, and the extracellular matrix (ECM) to coordinate growth and differentiation. Here, we use the Drosophila embryo as a model to investigate how BMP responses are influenced by a cell's local ECM environment. We show that integrins, which are ECM receptors, are absolutely required for peak BMP signaling. This stimulatory effect of integrins requires their intracellular signaling function, which is activated by the ECM protein collagen IV. Mechanistically, integrins interact with the BMP receptor and stimulate phosphorylation of the downstream Mad transcription factor. The BMP-pathway-enhancing function of integrins is independent of focal adhesion kinase, but it requires conserved NPXY motifs in the β-integrin cytoplasmic tail. Furthermore, we show that an α-integrin subunit is a BMP target gene, identifying positive feedback between integrin signaling and BMP pathway activity that may contribute to robust cell fate decisions.
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