Invited Talk ESA-SRB-ANZOS 2025 in conjunction with ENSA

Calcium (Ca²⁺) signals initiate embryo development at fertilization and are frequently disrupted in human assisted reproduction, which is associated with metabolic abnormalities in children. In mice, excess or inadequate Ca²⁺ signals at fertilization impair embryo development and alter adult metabolism, but the mechanisms are unknown. In this lecture, I will describe our work showing that excess Ca²⁺ signaling in one-cell mouse embryos alters the production of epimetabolites required for nuclear reprogramming and zygotic genome activation (ZGA). Mechanistically, excess Ca²⁺ increases pyruvate dehydrogenase activity, increasing acetyl-CoA production and decreasing lactate and presumably lactyl-CoA availability. These changes disrupt epigenetic marks including H3K27ac and H3K18la, impair ZGA by reducing RNA polymerase I activity, and compromise preimplantation embryo development. Exogenous lactyl-CoA rescues H3K18la, ZGA, and embryo development. These studies demonstrate that Ca²⁺ dynamics drive metabolic regulation of epigenetic reprogramming at fertilization, resulting in long-term offspring metabolic abnormalities.