Differential expression of imprinted genes in normal and IUGR human placentas

Abstract

Genomic imprinting refers to silencing of one parental allele in the zygotes of gametes depending upon the parent of origin.  Loss of imprinting (LOI) is the gain of function from the silent allele that can have a maximum effect of doubling the gene dosage. LOI may play a significant role in the etiology of intrauterine growth restriction (IUGR). Using placental tissue from 10 normal and 7 IUGR pregnancies, we conducted a systematic survey of the expression of a panel of 74 “putatively” imprinted genes using quantitative RT-PCR. We found that 52/74 (~70%) of the genes were expressed in human placentas. Nine of the 52 (17%) expressed genes were significantly differentially expressed between normal and IUGR placentas; 5 were up-regulated (PHLDA2, ILK2, NNAT, CCDC86, PEG10) and 4 down-regulated (PLAGL1, DHCR24, ZNF331, CDKAL1). We also assessed LOI profile of 14 imprinted genes in 14 normal and 24 IUGR placentas using a functional and sensitive assay developed in our laboratory. Little LOI was observed in any placentas for 5 of the genes (PEG10, PHLDA2, MEG3, EPS15, CD44).  With the 149 heterozygosities examined, 40 (26.8%) exhibited LOI > 3%. Some genes exhibited frequent LOI in placentas regardless of the disease status (IGF2, TP73, MEST, SLC22A18, PEG3), while others exhibited LOI only in IUGR placentas (PLAGL1, DLK1, H19, SNRPN). Importantly, there was no correlation between gene expression and LOI profile. Our study suggests that genomic imprinting may play a role in IUGR pathogenesis, but mechanisms other than LOI may contribute to dysregulation of imprinted genes.