Abstract: Ibrahim Ömer ÇIÇEK

miRNAs as global effectors of nutritional readjustment of gene expression

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Ibrahim Ömer Çiçek, Halyna Shcherbata

IMPRG of Gene Expression and Signaling, Max Planck Institute, Göttingen, Germany.

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The ability of an organism to adapt to changing environmental conditions is essential for its fitness and survival. The adaptation involves behavioral and physiological changes, both of which are initiated and controlled with great precision by the molecular machineries within each cell. Cellular responses to these alterations are exerted as changes in gene expression, which is controlled in every step through transcription and translation of each gene. miRNAs are such fine-tuning elements for precise gene expression control. They are short noncoding RNA molecules that regulate gene expression post-transcriptionally by affecting mRNA stability and availability for translation. They have been shown to act on diverse cellular and physiological processes such as cell survival, death, and fate determination. In addition, miRNAs’ expression is known to be dynamically affected by intrinsic and extrinsic changes such as development, nutrition, ageing and other stress. Continuous generation of adult tissues from their respective adult stem cells is tightly regulated especially in accordance to environmental favorability. Stem cell divides asymmetrically into another stem cell and a daughter that undergoes differentiation to regenerate the respective adult tissue. In order to stay a stem cell, adult stem cells must remain in their niche. An open question of great importance is how the niche senses environmental changes and controls stem cell division, self-renewal, and differentiation accordingly. We have found that the recently evolved miR-310s complex in Drosophila melanogaster is expressed dynamically in various tissues throughout development. Loss of miR-310s resulted in reduced longevity, higher fat accumulation, and lower fecundity. Global changes in protein expression are investigated by heavy isotope labeling of proteins followed by quantitative mass spectrometry (SILAC). Among different misregulated protein groups, we focused on a nutrition associated cluster, particularly on lipid metabolism. We use Drosophila ovary as a model system to study the specificity of cell division and differentiation, since the ovarian soma bears different types of stem cells; the germline and somatic stem cells. The division of both types is required for egg production, a process known to be highly energy dependent and, hence, sensitive to nutritional stress. To identify one of the direct targets of miR-310s, we focused on the ovarian phenotypes where the deletion of miR-310s results in multilayered epithelia and fused egg chamber phenotypes that are dramatically enhanced upon nutritional stress. We found that Rab23, a negative regulator of highly evolutionary conserved Hedgehog (Hh) pathway, is a miR-310s target in ovarian somatic cells. It is well known that Hh signaling regulates the generation of the follicular epithelium and cooperates with TGF-?, Wg, and JAK/STAT signaling to control the somatic follicle stem cell proliferation that also is extremely sensitive to external and internal cues. Our data imply that the strength of Hh signaling is adjusted by miR-310s in response to dietary changes.