A Critical Role for Imprinted Genes in the Placenta in the Developmental Origins of Health and Disease

Abstract

Genomic imprinting is a form of non-Mendelian inheritance in which epigenetic mechanisms regulate monoallelic gene expression in a parent-of-origin-dependent manner. Imprinted genes play a pivotal role in the development of the fetus and extra-embryonic tissues, such as the placenta. The placenta is a temporary organ that is critical for interpreting complex biological cues between the mother, her developing child, and the surrounding environment. Alterations to placental function can occur on an epigenomic level and are widely recognized as having both immediate perinatal consequences as well as influencing the life-long health of the offspring. As a result, the placenta is an organ of intense interest in the growing field of the developmental origins of health and disease (DOHaD). This goal of this research was to explore the role of genomic imprinting not only as it relates to placental and fetal development, but also as a link to later-in-life disease. Using placental samples collected from the Extremely Low Gestational Age Newborn (ELGAN) cohort, we assessed the relationship between CpG DNA methylation of imprinted genes and: (1) risk of being born intrauterine growth restricted, (2) disruptions in childhood growth trajectories associated with risk of childhood obesity, and (3) the association with maternal pre-pregnancy BMI. Through these studies, we demonstrated that alterations in CpG methylation levels of imprinted genes within the placenta are associated with in utero and childhood health outcomes, and that maternal pre-pregnancy BMI may contribute to the observed perturbations in imprinting within the placenta. Moreover, we found a strong sexually dimorphic response, with both specific imprinted genes as well as broad biological functions showing distinct patterns dependent on fetal sex. These studies highlight the complex biologic and external factors which contribute to aberrant imprinting, leading to disease, and taken together these findings elucidate a critical role for imprinted genes in DOHaD.Doctor of Philosoph