RT Journal Article SR Electronic T1 Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.06.15.152868 DO 10.1101/2020.06.15.152868 A1 Mirna Marinić A1 Katelyn Mika A1 Sravanthi Chigurupati A1 Vincent J. Lynch YR 2020 UL http://biorxiv.org/content/early/2020/06/15/2020.06.15.152868.abstract AB The developmental origins and evolutionary histories of cell types, tissues and organ systems contribute to the ways in which their dysfunction leads to disease. In mammals for example, the nature and extent of maternal-fetal interactions, how those interactions develop, and their evolutionary history likely influence diseases of pregnancy such as infertility and preterm birth. Here we show genes that evolved to be expressed at the maternal-fetal interface in Eutherian (Placental) mammals play essential roles in the evolution of pregnancy and are associated with immune system disorders and preterm birth. Among these genes is the transcription factor HAND2, which suppresses estrogen signaling thereby allowing blastocyst implantation, indicating that the suppression of estrogen signaling during pregnancy is an innovation of Eutherian mammals. We found that HAND2 is dynamically expressed in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to reach a low at term. HAND2 regulates a small but distinct set of target genes in endometrial stromal fibroblasts including the cytokine IL15, which was also dynamically expressed throughout the menstrual cycle and gestation, and promoted the migration of natural killer cells and extravillous cytotrophoblasts. Remarkably, we found that the HAND2 promoter loops to a distal enhancer containing SNPs implicated in the regulation of gestation length and birth weight. Collectively, these data implicate HAND2 expression at the maternal-fetal interface, with the evolution of implantation and gestation length regulation, and preterm birth.Competing Interest StatementThe authors have declared no competing interest.