Congenital heart defects affect around 1% of newborn humans. Previous work has suggested that problems with the placenta might be one cause of aberrant heart development. To explore this link in more detail, Zhongzhou Yang and colleagues focus on the Slc25a1 gene, which encodes a mitochondrial citrate carrier and the loss of which has been linked with congenital heart defects. They show that mouse embryos lacking Slc25a1 develop both heart defects and placental defects. Specifically knocking out Slc25a1 in the developing heart does not affect heart development, but knocking out Slc25a1 only in the placental tissue is sufficient to cause placental and heart defects. Loss of Slc25a1 expression in placental cells also results in disrupted cytosolic citrate levels and decreased acetylation of histone 3 lysine 27 (H3K27) at the enhancers and promoters of genes associated with placental cell development. RNA sequencing shows that levels of pregnancy-specific glycoproteins (PSGs), which are produced by the placenta and are known to help regulate endothelial development, are also reduced in the Slc25a1 knockouts. Crucially, administering human PSG1 to pregnant mice lacking SLC25A1 partly rescues the placental and heart defects. Overall, this study clarifies the link between placental development and congenital heart defects, and identifies a potential new treatment strategy.
