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The role of Nuclear factor NF-Y in nutrient-mediated tissue turnover

ABSTRACT: Cellular turnover is the process of replacing old or damaged cells with new ones in the intestinal epithelium. The intestinal turnover relies on dietary cues, mediated by nutrient-sensing pathways, to regulate the balance between cell division and cell death. Several signaling pathways, including the target of rapamycin (mTOR), are known to play a role in this process. However, specific mechanisms of how nutrient-sensing pathways adjust intestinal turnover remain unclear. My unpublished results show that silencing of NF-Y in ISCs disrupts cellular turnover, cell adhesion, and cell communication, leading to excessive cell delamination into the intestinal lumen and the development of dysplastic changes in the intestinal epithelium. mRNA sequencing from ISCs shows that NF-Y regulates several genes related to the activity of the nutrient-sensing mTOR pathway. As a result, silencing NF-Y in ISCs leads to the activation of the mTOR pathway and the emergence of enlarged immature cells. Inhibition of the mTOR pathway genetically, through calorie restriction or through rapamycin feeding, prevents the NF-Y phenotype. These data show that NF-Y is a novel regulator of intestinal turnover in response to nutrients. The results from this project can enhance our understanding of how nutrient-sensing pathways are regulated in pathologies related to epithelial turnover.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE317617 | GEO | 2026/03/31

REPOSITORIES: GEO

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Project description:Mitochondrial oxidative function is tightly controlled to maintain energy homeostasis in response to nutrient and hormonal signals. An important cellular component in the energy sensing response is the target of rapamycin (TOR) kinase pathway; however whether and how mTOR controls mitochondrial oxidative activity is unknown. Here, we show that mTOR kinase activity stimulates mitochondrial gene expression and oxidative function. In skeletal muscle cells and TSC2-/- MEFs, the mTOR inhibitor rapamycin largely decreased gene expression of mitochondrial transcriptional regulators such as PGC-1alpha and the transcription factors ERRalpha and NRFs. As a consequence, mitochondrial gene expression and oxygen consumption were reduced upon mTOR inhibition. Using computational genomics, we identified the transcription factor YY1 as a common target of mTOR and PGC-1alpha that controls mitochondrial gene expression. Inhibition of mTOR resulted in a failure of YY1 to interact and be coactivated by PGC-1alpha. Notably, knock-down of YY1 in skeletal muscle cells caused a significant decrease in mRNAs of mitochondrial regulators and mitochondrial genes that resulted in a decrease in respiration. Moreover, YY1 was required for rapamycin-dependent repression of mitochondrial genes. Thus, we have identified a novel mechanism in which a nutrient sensor (mTOR) balances energy metabolism via transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer. Experiment Overall Design: Using Affymetrix MOE430 v2 gene chips, biological triplicates of each condition were analyzed: vehicle-treated, rapamycin-treated, gfp-infected, and pgc-1alpha-infected resulting in a total of 12 samples. Experiment Overall Design: Data were analyzed by RMA (with default settings) in BioConductor 1.2 -- one batch for the Rapamycin vs. Vehicle, and another batch for the PGC vs GFP.

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The role of Nuclear factor NF-Y in nutrient-mediated tissue turnover

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