Epigenetic effect of the ketone body beta-hydroxybutyrate on histone beta-hydroxybutyrylation in bovine cumulus-oocyte complexes

• Grant number: 18/09552-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: August 28, 2018
• End date: August 27, 2019
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Animal Reproduction
• Principal Investigator: Flávio Vieira Meirelles
• Grantee: Juliano Rodrigues Sangalli
• Supervisor: Pablo Juan Ross
• Host Institution: Faculdade de Zootecnia e Engenharia de Alimentos (FZEA). Universidade de São Paulo (USP). Pirassununga , SP, Brazil
• Institution abroad: University of California, Davis (UC Davis), United States
• Associated to the scholarship: 16/13416-9 - Use of the ketone body beta-hydroxybutyric acid as an experimental tool to study the link among metabolism, epigenetic and reproduction in cattle, BP.PD

Abstract

The fertility of dairy cows has declined in the past half-century, and the metabolic disturbances (e.g. Negative Energy Balance (NEB)) incurred by high-yielding cows are believed to be the main reason for poor reproductive performance. NEB is characterized by elevated levels of nonesterified fatty acids (NEFAs) and ketone bodies (i.e., acetone, acetoacetate and ²-hydroxybutyrate) in the blood serum. These molecules are known to affect the ovarian follicle, the microenvironment where the cumulus-oocyte complexes (COCs) matures, culminating in reduced fertility. Previously considered a "metabolic poison", BOHB has recently been shown to acts as an epigenetic modulator. Recently, it was identified a new type of histone mark, histone ²-hydroxybutyrylation (Kbhb), that is dramatically induced in response to elevated ²-hydroxybutyrate levels in cultured cells and liver of fasted animals. An understanding of these critical and diverse novel epigenetic events triggered by BOHB might give clues leading to better management of common disorders in dairy cows, such as ketosis and reproductive failure. On this basis, we are proposing a series of interconnected experiments to (1) To investigate the genome-wide distribution of histone ²-hydroxybutyrylation (H3K9bhb) in cumulus cells from COCs treated or not with the ketone body ²-hydroxybutyrate; (2) To analyse the messengers RNAs (RNA-seq) abundance in cumulus cells from COCs treated or not with the ketone body ²-hydroxybutyrate to comprehensively characterize the alterations on gene expression. This research project will offer a new avenue to study chromatin regulation and diverse functions of ²-hydroxybutyrate in the context of important bovine pathophysiological states, including negative energy balance, ketosis and reproductive failures. (AU)