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The Role of ATF4 as a Mediator of the Hexosamine Biosynthesis Pathway in Intestinal Stem Cells

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Title: The Role of ATF4 as a Mediator of the Hexosamine Biosynthesis Pathway in Intestinal Stem Cells
Author(s): Henriksson, Roselia
Contributor: University of Helsinki, Faculty of Agriculture and Forestry
Degree program: Master 's Programme in Microbiology and Microbial Biotechnology
Specialisation: no specialization
Language: English
Acceptance year: 2022
Abstract:
Tiivistelmä — Referat — Abstract Intestine renews itself from intestinal stem cells (ISCs) in response to cell damage and disease. Damaged and dead cells are replaced by ISCs through cell division followed by daughter cell differentiation. Disturbances in this process can lead to diseases such as cancer. Hexosamine biosynthetic pathway (HBP) is a mediator of systemic insulin signaling induced ISC proliferation. However, the full molecular mechanism of HBP mediated ISC proliferation is yet to be discovered. Deciphering the mechanisms of the regulation responsible for ISC renewal could pave way for disease etiology dependent on the rate of ISCs proliferation. In this project I use Drosophila genetic tools to elucidate transcriptional and translational level control of HBP regulated ISC proliferation. Glutamine Fructose-6-phosphate Amidotransferase (GFAT) activity limits the rate of N-Acetylglucosamine GlcNAc and consequently ISC proliferation. Thus, gfat2Δ1 mutant flies are used to study molecular regulation of HBP. Full midguts of Drosophila will be imaged using Aurox Clarity Spinning-disc Confocal system. Confocal 3D images will be analyzed using an image analysis software called linear analysis of midgut (LAM) to retain region specific data. Exploring ISC proliferation in relation to nutrient sensing pathways in the full midgut level is still novel and LAM provides region specific data in previously unprecedented detail. The end product of HBP pathway Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) was supplemented within the diet of the flies to observe its effect to the gfat2Δ1 ISC phenotype. UDP-GlcNac did not rescue the gfat2Δ1 ISCs. Usage of Drosophila genetic tools elucidated previously unknown transcriptional level regulation of HBP induced ISC proliferation: ATF4 knockdown in gfat2Δ1 mutant ISCs rescued gfat2Δ1 attenuated ISC division. In addition, ATF4 was indicated to possibly regulate the gfat2Δ1 phenotype via the regulation of growth through ribosome biogenesis and 4EBP translation inhibition. This study revealed the mediator of HBP, the transcription factor ATF4 to be the modulator of ISC proliferation.
Keyword(s): ATF4 Hexosamine biosynthesis pathway intestinal stem cells nutrients


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