Glucose as a fetal nutrient: dynamic regulation of several glucose transporter genes by DNA methylation in the human placenta across gestation

The human placenta ensures proper fetal development through the regulation of nutrient and gas transfer from the mother to the fetus and the removal of waste products from the fetal circulation. Glucose is one of the major nutrients for the growing fetus. Its transport across the placenta to the fetus is mediated by a family of facilitative transporter proteins, known as the glucose transporters (GLUTs), encoded by the SLC2A family of genes. There are 14 members of this gene family, and the expression of several of these has been shown in human placenta; however, aside from GLUT1 and GLUT3, little is known about the role of these proteins in placental function, fetal development and disease. In this study, we analysed previously generated genome-scale DNA methylation and gene expression data to examine the role of methylation in GLUT expression throughout gestation. We found evidence that DNA methylation regulates expression of GLUT3 and GLUT10, while the constitutively expressed GLUT1 showed no promoter methylation. We further analysed the level of DNA methylation across the promoter region of GLUT3, previously shown to be involved in glucose back-flux from the fetal circulation into the placenta. Using the Sequenom EpiTYPER platform, we found increasing DNA methylation of this gene in association with decreasing expression as gestation progresses, thereby highlighting the role of epigenetic modifications in regulating the GLUT family of genes in the placenta during pregnancy. These findings warrant a reexamination of the role of additional GLUT family members in the placenta in pregnancy and disease.