The Nuclear Localization of ACLY Guards Early Embryo Development Through Recruiting P300 and HAT1 to Promote Histone Acetylation and Transcription

Abstract Metabolic processes and epigenetic reprogramming are intricately interconnected; however, their mechanistic interplay remains unclear. This study elucidates the role of ATP‐citrate lyase (ACLY), an essential enzyme in acetyl‐CoA production that uniquely localizes to the nucleus in oocytes and early embryos. Maternal Acly deletion in oocytes preserves fertility due to the compensatory upregulation of Acetyl‐CoA Synthetase 2 (ACSS2), whereas zygotic Acly knockout causes developmental arrest at the pre‐blastocyst stage without ACSS2 induction. Mechanistically, nuclear ACLY recruits and interacts with histone acetyltransferases, specifically E1A binding protein p300 (P300) and histone acetyltransferase 1 (HAT1), supplying acetyl‐CoA for histone acetylation to activate transcription, which is essential for embryogenesis. Clinically, enhanced ACLY nuclear localization correlates with superior quality of human embryos. Functionally, AKT‐mediated phosphorylation (Thr447/Ser451/Ser455) drives the nuclear translocation of ACLY and facilitates its interaction with HAT1 and P300. Inhibition of ACLY or its phosphorylation disrupts the promoting effects of AKT activators, such as insulin‐like growth factor‐1 (IGF‐1), on blastocyst formation. These findings suggest that ACLY is a metabolic hub that bridges signaling and epigenetic remodeling, ensuring acetyl‐CoA availability for chromatin modifications, and offering insights into the metabolic determinants of embryo viability and potential therapeutic targets for infertility.