Metabolic Reprogramming of Iron Endows the Function of ISCA2-TET Interaction During Peri-implantation Development

Metabolic reprogramming plays important roles in embryo development. However, the metabolic network has still not been systematically investigated during the processes. In this study, we develop MFE, a metabolites flux estimation tool, to predict metabolite abundances and their regulons, highlighting the role of Fe(II) and its regulon-ISCA2, in the inner cell mass (ICM) of human and mouse blastocysts. By introducing Isca2-/-, Isca2G77S/G77S and Isca2C144S/C144S mice, we find ISCA2 binding with iron, but not Fe-S cluster, is indispensable for mouse peri-implantation development. Mechanistically, nuclear ISCA2 interacts with TET, and Fe(II) is important for the interaction by triggering the enzymatic activity of TET. The partnership safeguards promoters of epiblast-specific genes from hypermethylation and is essential for epiblast development in mouse peri-implantation embryos. The study provides insights into how iron metabolism modulates embryo development, and suggests a manner of Fe(II)-dependentenzymes to achieve activity under physiological conditions. Overall design: RNA-seq, small RNA-seq, EM-seq of mouse Isca2 WT and KO pre-implantation embryos. To collected pre-implantation embryos, Isca2+/- female mouse intraperitoneal with 6.5 international unit of pregnant mares' serum gonadotropin and, 45 to 47 h later, with 5 IU of human chorionic gonadotropin and crossed to Isca2+/- males.