Silencing of retrotransposon-derived imprinted gene RTL1 is the main cause for postimplantational failures in mammalian cloning

Significance To investigate the epigenetic mechanism of pregnancy failure in mammals, we exploited the high rate of fetal loss in pig induced pluripotent stem cell (iPSC) nuclear transfer. We generated methylomes of pig iPSCs and associated nuclear transfer embryos from reciprocal crosses between two distinct pig breeds. Our methylome analysis revealed that misregulation of RTL1 as the principal basis of pregnancy failure using pig iPSCs. Remarkably, RTL1 has broad fertility implications across mouse, rat, pig, cattle, and human from nuclear transfer cloning, tetraploid complementation, and artificial insemination, to natural fertilization. In all of these procedures, low RTL1 expression consistently corresponds to pregnancy failures.