The potential role of Fibrillin 2 in equine placental and fetal development

Abstract

Energy adaption in pregnant dams is a vital process to appropriately supply the energy requirements to the fetus through the placenta (Yu et al. EMBO Reports (2020); Fowden et al. Equine vet. J. (1984) 16 (4), 239-246). The placenta is a transient organ with a crucial role in the survival and development of the fetus by providing nutrients, removing waste, and secreting hormones and growth factors. To understand the dynamics of the genes responsible for placental function, we recently investigated the equine placental DNA methylome. Chorioallantois (CA) samples were collected from healthy pregnant mares at different gestational time points (4, 6, and 10 months; n=3 for each time point). DNA was extracted and RRBS (Reduced Representation Bisulfate Sequencing) was performed. We then combined the methylome data with available transcriptomic profiles of the same samples to better detail the placental gene expression dynamics. Based on the reverse relationship between methylation and gene expression, we identified 18 genes with higher expression and lower methylation at 4 months compared to the other time points, including Fibrillin 2 (FBN2). Given the known high expression pattern of FBN2 in the human placenta, especially during early pregnancy in cytotrophoblasts, we decided to further detail its potential role in equine placental development. FBN2 encodes a peptide hormone called placensin that is secreted by trophoblasts and increases cAMP-PKA signaling. In humans, placensin increases gluconeogenesis and glucoserelease which stimulate cAMP release and PKA activity in maternal circulation and therefore, acts as a placental gluconeogenic hormone that increases in serum as pregnancy advances and the insulin resistance level increases. The changes in the glucose level and insulin resistance have also been documented in horses, however, the underlying mechanism has not yet been identified (Fowden et al. Equine vet. J. (1984) 16 (4), 239-246; George et al. Am J Vet Res 2011; 72:666–674). Our preliminary data suggests a possible involvement of FBN2 in gluconeogenesis in mares given its expression pattern. Since maternal glucose is the main source of energy for the fetus, any alteration in maternal glucose and insulin could have an effect on fetal development, which has been described in other species such as sheep (Yu et al. EMBO Reports (2020)). Further detailing the expression dynamics of FBN2 in placenta and placensin in maternal blood could aid elucidation of the mechanisms for glucose homeostasis in pregnant mares. Then, such analyses may be expanded to the additional genes showing similar expression dynamics to further highlight their potential role in placental development. This project was supported by the Center for Equine Health with funds provided by the State of California satellite wagering fund and contributions by private donors.