Organellar Remodelling of Lipids Determines the Epigenetic Reprogramming and Maternal-to-Zygotic Transition in Early Development
Metabolic reprogramming of glucose and amino acids has been documented to affect early development. Here, we show that peroxisome-mediated ß-oxidation is involved in lipids reprogramming to achieve H3K4me3 erasure and then zygotic genome activation (ZGA) in early embryo development. The metabolic patterns of fatty acids (FAs), triglyceride (TG) and phospholipid (PL) are reprogrammed during the oocyte-to-embryo transition. Very long-chain fatty acids (VLCFAs), arachidonic acid (ARA), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (Lyso-PE), lysophosphatidylcholine (Lyso-PC), and methyl donors are stored in oocytes, and after fertilization, they are converted into phosphatidylcholine (PC) at the 2-cell stage. Mitochondrial ß-oxidation prevails in oocytes, while peroxisomal ß-oxidation plays a critical role in shortening the VLCFA to form TG and synthesize PC and balancing the ratio of saturated and unsaturated FAs, which consumes the methyl donors as conducive to H3K4me3 erasure at the 2-cell stage. Inhibiting the peroxisome-mediated ß-oxidation disrupts lipids metabolism remodellingH3K4me3 erasure and subsequent ZGA, leading to embryo arrest at the 2-cell stage. Oocytes from obese mice show I a relatively low level of VLCFAs, defective peroxisomal ß-oxidation, and incomplete H3K4me3 erasure and ZGA. Microinjection of two saturated fatty acids, palmitic and myristic acids, rescues 2-cell arrest caused by peroxisome-mediated ß-oxidation inhibition and obesity, and overexpressing Pemt to consume the methyl donors has the same rescue effect. These results elucidate a novel link among the peroxisomal-ß-oxidation-mediated lipid metabolism reprogramming, H3K4me3 modification and ZGA during oocyte-embryo transition, and may provide a unique approach to improve reproduction in obese women. Overall design: Control embryos at 2-cell stages and siAcox1 embryos at 2-cell embryos for three replicates are performed RNA sequencing.