Deciphering the role of the sugar-induced transcription factor, Mondo in Drosophila Melanogaster

Huang, Hui-Lan (2020): Deciphering the role of the sugar-induced transcription factor, Mondo in Drosophila Melanogaster. Dissertation, LMU München: Medizinische Fakultät

Abstract

Overconsumption of sugar promotes the occurrence of metabolic disorders. Therefore, studying the mechanisms underlying our physiological responses to sugar helps identify the underlying molecular mechanisms and potential therapeutic targets. Mondo family transcription factors are evolutionarily conserved across a number of species including Drosophila melanogaster, and they are known as the key “sugar sensor” in our body. Lines of evidence indicate that this component is misregulated in insulin resistance and diabetes. The aims of my PhD thesis are to determine the function of fly Mondo and its interacting partner Mlx during different stages and in different nutrition states, and to globally identify its direct target genes and regulated pathways. A deficiency in Mondo and Mlx causes sugar inviability in flies fed on a high sugar diet. Furthermore, Mondo is essential for survival during starvation after sugar deprivation, which brings our attention to the involvement of Mondo in the regulation of nutrient usage and metabolic adaptation during starvation. The chromatin Mondo-Mlx binding profile reveals several known sugar-dependent Mondo target sites and potential new targets. The identified target genes are functionally clustered in metabolic pathways regarding sugar, lipid, and amino acids, which supports the concept that Mondo is a master metabolic regulator. Importantly, the data indicates that Mondo-Mlx is at the top of a regulatory network composed of abundant secondary transcriptional effectors. Motif searching analysis shows some interesting findings: in addition to the canonical ChoRE motif, a putative novel Mondo binding motif was also identified. Finally, our RNA Pol II ChIP-seq data provides the first direct evidence indicating that Mondo acts as both a transcriptional activator and repressor for different target genes and regulates gene transcription via influencing Pol II recruitment or elongation. Less is known about the role of Mondo family proteins in the nervous system, although Mondo expression has previously been observed in this metabolically active organ system. Here, I provide evidence of Mondo’s role in the central nervous system’s metabolism of sugar, lipids, and amino acids, specifically in the amino acids serine, glycine, and glutamine. Interestingly, the metabolism of lipid and serine in the fly brain has been shown to determine sleeping behaviors, though further investigation is necessary to test whether Mondo has a systemic role in controlling sleeping behaviors.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 17. November 2020
• 1. Bericht­erstatter:in: Ladurner, Andreas