Altered gene expression and methylation of the human chromosome 11 imprinted region in small for gestational age (SGA) placentae

Abstract

Imprinted genes are known to be crucial for placental development and fetal growth in mammals, but no primary epigenetic abnormality in placenta has been documented to compromise human fetal growth. Imprinted genes demonstrate parent-of-origin-specific allelic expression that is epigenetically regulated i.e. extrinsic to the primary DNA sequence. To undertake an epigenetic analysis of poor fetal growth in placentae and cord blood tissues, we first established the tissue-specific patterns of methylation and imprinted gene expression for two imprinting clusters (KvDMR and H19 DMR) on chromosome 11p15 in placentae and neonatal blood for 20 control cases and 24 Small for Gestational Age (SGA) cases. We confirmed that, in normal human placenta, the H19 promoter is unmethylated. In contrast, most other human tissues show paternal methylation. In addition, we showed that the IGF2 DMR2, also paternally methylated in most human tissues, exhibits hypomethylation in placentae. However, in neonatal blood DNA, these two regions maintain the differential methylation status seen in most other tissues. Significantly, we have been able to demonstrate that placenta does maintain differential methylation at the imprinting control regions H19 DMR and KvDMR. Of note, in one SGA placenta, we found a methylation alteration at the H19 DMR and concomitant biallelic expression of the H19 gene, suggesting that loss of imprinting at H19 is one cause of poor fetal growth in humans. Of particular interest, we demonstrated also a decrease in IGF2 mRNA levels in all SGA placentae and showed that the decrease is, in most cases, independent of H19 regulation.

Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth

“…9 Here, we extend these studies to show that this relationship holds across the range of normal birth weight. Previous studies have reported decreased IGF2 expression in placenta from SGA pregnancies, 9,16 which may occur from early on in pregnancy, 35 and studies in mice confirm that IGF2 controls a substantial part of fetal growth.…”

“…[4][5][6][7] In addition, altered placental expression of imprinted genes has been reported in association with human fetal growth restriction. [8][9][10] The imprinted insulin-like growth factor 2 (IGF2) gene has a major role in the matching of placental nutrient supply to fetal demand, 4 and altered IGF2 expression has been reported in association with fetal growth restriction in humans. 9,10 IGF2, and the neighboring H19 gene, are situated in an imprinted gene cluster on human chromosome 11p15.…”

“…[8][9][10] The imprinted insulin-like growth factor 2 (IGF2) gene has a major role in the matching of placental nutrient supply to fetal demand, 4 and altered IGF2 expression has been reported in association with fetal growth restriction in humans. 9,10 IGF2, and the neighboring H19 gene, are situated in an imprinted gene cluster on human chromosome 11p15. Expression of the paternally expressed IGF2 and the maternally expressed H19 is controlled by differential methylation at imprinting control region 1 (ICR1), 11,12 which contains binding sites for the zincfinger CCCTC-binding factor (CTCF) protein.…”

Differential expression of imprinted genes in normal and IUGR human placentas

“…14 The role of genomic imprinting in IUGR pregnancies has been investigated, but systematic studies are sparse. 15,16 A recent study comparing gene expression profiles of normal and IUGR placentas using microarrays which included 27 imprinted genes demonstrated that 22% of the imprinted genes were differentially expressed, far in excess of the non-imprinted genes. 7 These results strongly demonstrate a critical role of genomic imprinting in placental/fetal growth and suggest that IUGR may be a result of altered expression of critical imprinted genes.…”

Frequency and characterization of DNA methylation defects in children born SGA

“…6 Results have been very heterogeneous with most studies analyzing chorionic villi or placenta tissue. [12][13][14][15] Nevertheless, placental tissue displays an intermediate distribution of methylation as compared, for example, with embryonal epithelial cells. 16,17 Moreover, there is greater epigenetic variation in extraembryonic than in embryonic tissue.…”