WNT2 promoter methylation in human placenta is associated with low birthweight percentile in the neonate

Neonates with birthweights below the tenth percentile for gestational age are considered small for gestational age (SGA). Such infants have an increased risk for perinatal mortality and morbidity as well as an increased lifetime risk for adult onset disorders. Low birth weight percentile is etiologically heterogeneous and may result from maternal, fetal, placental and environmental factors. However, the molecular determinants of human SGA are not well elucidated. We proposed that fetal growth potential could be negatively impacted by the epigenetic dysregulation of specific genes in the placenta. Using methyl DNA immunoprecipitation coupled with Agilent CpG island microarrays, we analyzed the differences in DNA methylation between placentas of eight SGA neonates and eight controls with birthweight percentiles above the tenth percentile. We identified several candidate genomic regions with differential DNA methylation between the two groups. The DNA methylation differences identified in the promoter of the WNT2 gene were prioritized for further study in an extended cohort of 170 samples given the important function of this gene in mouse placental development and its high expression in human placenta. High WNT2 promoter methylation (WNT2PrMe) was found only in placental tissue and not in the cord blood of the fetus. It was significantly associated with reduced WNT2 expression in placenta and with low birthweight percentile in the neonate. Our results show that WNT2 expression can be epigenetically downregulated in the placenta by DNA methylation of its promoter and that high WNT2PrMe is an epigenetic variant that is associated with reduced fetal growth potential. Note: All of the array data in the manuscript can be accessed from the Gene Expression Omnibus (GEO) NCBI database under GEO accession number GSE22326.