Chromatin remodeler developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders

Abstract

Alcohol affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. To explore the etiology of FASD, we collected an exceptional cohort of 80 severely alcohol-exposed and 100 control newborns and performed genome-wide DNA methylation and gene expression analyses of placentas. DPPA4, FOXP2, and TACR3 with significantly decreased DNA methylation were discovered - particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When human embryonic stem cells (hESCs) were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNA methylation similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNA methylation changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development. Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.