Intergenerational inheritance induced by high levels of cholesterol in C. elegans is due to vitellogenin and controlled by miRNA

Author(s)

Willian Goulart Salgueiro

• Document type: Master's Dissertation
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2020-08-28

Examining board members

Daiana Silva Avila; Fabio Papes

• Advisor: Marcelo Alves da Silva Mori

Abstract

Cholesterol is essential to many physiological processes, mainly for its structural function and as a precursor for a number of endocrine signaling molecules. However, its excessive intake in a western diet may lead to obesity and to different dyslipidemia, what might be translated into an increased risk for metabolic and cardiovascular diseases. Beyond that, there is a number of evidences showing that parents with metabolic diseases, including those associated with high cholesterol, may give birth to an offspring that has metabolic alterations even though it never got in contact with any of their causing factors. Such possibility is alarming, once it might allow the perpetration of those possibly deleterious disturbances through epigenetic mechanisms. Basic research in this field could be limited by costs and time needed for mammals to give birth to a new generation. Hence, the nematode C. elegans is a viable alternative. This invertebrate does not synthesize cholesterol, and, because of that, cholesterol levels can be tightly controlled through the diet. Besides that, C. elegans genes are highly conserved in mammals so that hypotheses confirmed in the worm can be extended and applied to more complex organisms. Even more, for its short generational time, C. elegans are ideal for conducting research that include multiple generations. Here we show that C. elegans exposed to a high concentration of cholesterol (50 µM; 20 µg/mL) in P0 results in many several phenotypes that are inheritable by F1. Accelerated developmental timing due to high cholesterol seems to be due to a higher expression of vitellogenin, mainly vit-2/YP170B. Our data suggest that miRNAs positively regulate vit-2/YP170B expression in P0 and F1, what is sufficient to phenocopy high cholesterol exposure. We suggest that miRNA of the let-7 family (let-7-fam) regulate the expression of vit-2/YP170B, most likely in an indirect manner, providing a larger supply of yolk to the progeny, where an element is likely carried through the yolk complex to restart the cycle of expression of the same phenotype in the next generation, including upregulation of let-7-fam miRNAs and vit-2/YP170B. Our data points to a yet not stablished link between high cholesterol supply and the upregulation of vitellogenin expression by miRNAs (AU)

• FAPESP's process: 17/22057-5 - Physiological effects and transgenerational inheritance induced by cholesterol-rich diet in Caenorhabditis elegans
• Grantee: Willian Goulart Salgueiro
• Support Opportunities: Scholarships in Brazil - Master