Characterization of Histone Lysine β-hydroxybutyrylation in bovine tissues, cells, and cumulus-oocyte complexes

Besides their canonical roles as energy sources, short-chain fatty acids act as metabolic regulators of gene expression through the histone post-translational modifications. The ketone body {beta}-hydroxybutyrate (BHB) was shown to cause a novel type of epigenetic modification, Histone Lysine {beta}-hydroxybutyrylation (Kbhb), associated with genes upregulated in starvation-responsive metabolic pathways. Dairy cows increase BHB in early lactation and its effects on cellular epigenome are largely unknown. To unravel these effects, we sought and identified that Kbhb is present in bovine tissues in vivo and further confirmed that this epigenetic mark is responsive to BHB in bovine and human fibroblasts cultured in vitro in a dose-dependent manner. We also demonstrated that the maturation of cumulus-oocyte complexes with high concentrations of BHB did not affect the competence to complete meiotic maturation neither to develop until blastocyst stage. BHB treatment strongly induced H3K9bhb in cumulus cells, but this modification was only faintly detected in oocytes. Profiling the transcriptome in cumulus cells indicated that BHB treatment altered the expression of 345 genes. The down-regulated genes are mainly involved in glycolysis and ribosome assembly pathways, while the up-regulated genes are involved in mitochondrial metabolism and oocyte development. The specific genes and pathways altered by BHB treatment will provide entry points to carry out functional experiments aiming to mitigate problems and improve fertility in cattle suffering metabolic disorders. A key goal for future work will be to understand mechanistically how BHB transmits signals from the environment to affect cellular functions and the bovine epigenome. Summary sentenceBeta-hydroxybutyrate induces Histone Lysine {beta}-hydroxybutyrylation in fibroblasts and cumulus-oocyte complexes, it alters the transcriptome in cumulus cells, but does not affect oocytes competence to resume meiosis and develop until blastocyst stage.