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

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.

Erasing gametes to write blastocysts: metabolism as the new player in epigenetic reprogramming

“…The administration of exogenous ketone body β-hydroxybutyrate to mouse lead to increased global histone acetylation in several organs, but mostly the kidneys, due to HDAC inhibition (Shimazu et al, 2013). The same effect was observed after somatic cell nuclear transfer zygotes exposure to β-hydroxybutyrate, in which the hyperacetylation state of H3K9 remained until blastocyst stage (Sangalli et al, 2018).…”

Metabolism-associated genome-wide epigenetic changes in bovine oocytes during early lactation

“…Coupled with previous reports of developmental failure in oocytes matured with high NEFA concentrations, the fatty acid oxidation and degradation found in Mpp and CH oocytes could suggest a metabolic direction of fatty acid metabolism that favors developmental competence. Similarly, BHB acts as a histone deacetylase inhibitor in mice, but not in cows, although it has been shown to modulate lipid metabolism genes in bovine somatic cells 33,34 . Similarly, we suggest that exposure to such metabolites during Epp has an impact on the methylation of genes involved in cellular lipid metabolism.…”

Catalytic inhibition of H3K9me2 writers disturbs epigenetic marks during bovine nuclear reprogramming

“…Fibroblast cell line was obtained from a 55-days-old crossbred (Gir × Holstein; Bos indicus × Bos taurus ) fetus, as described previously 48 . Concisely, a skin biopsy (1 cm 2 ) was minced into small pieces with a scalpel blade, followed by digestion with 0.1% (w/v) collagenase for 3 h at 38.5 °C.…”