Evolutionary transcriptomics implicates <i>HAND2</i> in the origins of implantation and regulation of gestation length.

Abstract

The developmental origins and evolutionary histories of cell types, tissues, and organs contribute to the ways in which their dysfunction produces disease. In mammals, the nature, development and evolution of maternal-fetal interactions likely influence diseases of pregnancy. Here we show genes that evolved expression at the maternal-fetal interface in Eutherian mammals play essential roles in the evolution of pregnancy and are associated with immunological disorders and preterm birth. Among these genes is <i>HAND2</i>, a transcription factor that suppresses estrogen signaling, a Eutherian innovation allowing blastocyst implantation. We found dynamic <i>HAND2</i> expression in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to a low at term. HAND2 regulates a distinct set of genes in endometrial stromal fibroblasts including <i>IL15</i>, a cytokine also exhibiting dynamic expression throughout the menstrual cycle and gestation, promoting migration of natural killer cells and extravillous cytotrophoblasts. We demonstrate that <i>HAND2</i> promoter loops to an enhancer containing SNPs implicated in birth weight and gestation length regulation. Collectively, these data connect <i>HAND2</i> expression at the maternal-fetal interface with evolution of implantation and gestational regulation, and preterm birth.