Metabolic gene expression and epigenetic effects of the ketone body β-hydroxybutyrate on H3K9ac in bovine cells, oocytes and embryos

Sci Rep. 2018 Sep 13;8(1):13766. doi: 10.1038/s41598-018-31822-7.

Abstract

The rapid decline in fertility that has been occurring to high-producing dairy cows in the past 50 years seems to be associated with metabolic disturbances such as ketosis, supporting the need for research to improve our understanding of the relations among the diet, metabolism and embryonic development. Recently, the ketone body β-hydroxybutyrate (BOHB) was demonstrated to be a potent inhibitor of histone deacetylases (HDACs). Herein, we performed a series of experiments aiming to investigate the epigenetic effects of BOHB on histone acetylation in somatic cells, cumulus-oocyte complexes (COCs) and somatic cell nuclear transfer (SCNT) embryos. Treatment with BOHB does not increase histone acetylation in cells but stimulates genes associated with ketolysis and master regulators of metabolism. We further demonstrated that maturing COCs with high levels of BOHB does not affect their maturation rate or histone acetylation but increases the expression of PPARA in cumulus cells. Treatment of somatic cell nuclear transfer zygotes with BOHB causes hyperacetylation, which is maintained until the blastocyst stage, causing enhanced FOXO3A expression and blastocyst production. Our data shed light on the epigenetic mechanisms caused by BOHB in bovine cells and embryos and provide a better understanding of the connection between nutrition and reproduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / biosynthesis
  • 3-Hydroxybutyric Acid / genetics
  • 3-Hydroxybutyric Acid / pharmacology*
  • Acetylation
  • Animals
  • Blastocyst / cytology
  • Cattle
  • Cell Line
  • Cumulus Cells / metabolism
  • Embryo, Mammalian / cytology*
  • Embryonic Development / drug effects*
  • Female
  • Fertility / physiology*
  • Forkhead Box Protein O3 / biosynthesis
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Nuclear Transfer Techniques
  • Oocytes / metabolism*
  • Oxidative Stress / drug effects
  • PPAR alpha / biosynthesis
  • Pregnancy

Substances

  • Forkhead Box Protein O3
  • Histone Deacetylase Inhibitors
  • Histones
  • PPAR alpha
  • Histone Deacetylases
  • 3-Hydroxybutyric Acid