Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Diabetes alters the epigenetic landscape of the oocyte and early embryo. (#151)

Hannah M Brown 1 , Melissa A White 1 , Lesley J Ritter 1 , Jeremy G Thompson 1
  1. The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia

Early embryo development is an exquisitely sensitive period of the developmental continuum, profoundly influencing neonatal and adult health.  Maternal and paternal hyperglycaemia is associated with long term health complications including increased risk of miscarriage, altered birth weight, and increased incidence of diabetes and metabolic syndrome in adult life.  The mechanisms underlying this intergenerational transmission of disease remain unclear.  New evidence has implicated the ten-eleven-translocation (TET) family of chromatin-modifying enzymes in O-linked glycosyltransferase (OGT)-dependent histone glycosylation.  This led us to assess these systems in the mouse oocyte and early embryo.  We demonstrated co-precipitation of TET3 (the key TET family member in the oocyte and early embryo) and OGT.  In oocytes matured under hyperglycaemic conditions, we identified significant alterations to histone glycosylation (H3/H4).  Given O-linked glycosylation competes for residues also targeted by phosphorylation, we examined the abundance of known phospho-modifications on both H3 and histone variant H3.3.  Hyperglycaemia during IVM dramatically decreased the abundance of phosphorylation at H3S10P and H3S28P.  Interestingly, hyper-phosphorylation at H3.3S31, a serine only present in the H3.3 variant, occurred following oocyte maturation under diabetic conditions.  We also assessed alterations in histone landscape in the early embryo (pronuclear and 2-cell) following IVM and also in a streptozotocin-induced in vivo diabetic model and identified changes in key histone modifications, as well as the localisation of  glycosylated proteins in the nucleus.  This data represents the first evidence that maternal hyperglycaemia alters the histone landscape of the early embryo and identifies for the first time, a direct mechanism between maternal hyperglycaemia and intergenerational transmission of disease.