Human Fetal Growth Disorders and Imprinting Anomalies

Abstract

Epigenetic mechanisms play a key role in regulating gene expression. One of the best-studied epigenetic modifications is DNA methylation at cytosine residues of CpG dinucleotides in gene promoters, transposons and imprinting control regions (ICR). Genomic imprinting refers to the epigenetic marking of genes that results in monoallelic expression, depending on their parental origin. Several hormone genes involved in embryonic and fetal growth are imprinted. There are two critical time periods in epigenetic reprogramming: gametogenesis and early preimplantation development. Major reprogramming takes place in primordial germ cells in which parental imprints are erased and totipotency is restored. Imprint marks are then re-established during spermatogenesis or oogenesis, depending on sex. Upon fertilization, there is genome-wide demethylation followed by a wave of de novo methylation, both of which are resisted by imprinted loci. Disruption of imprinting causes disorders involving growth defects, such as the Beckwith-Wiedemann overgrowth syndrome (BWS) and Silver-Russell syndrome (SRS) with the opposite phenotype, involving intrauterine and postnatal growth retardation. These growth disorders are caused, in most cases, by abnormal DNA methylation at the 11p15 imprinted region that contains many imprinted genes, including Insulin-like Growth Factor 2 (IGF2). Loss of methylation (LOM) on the maternal allele at the centromeric ICR2/KCNQ1OT1 region or gain of methylation (GOM) on the maternal allele at the telomeric ICR1/IGF2/H19 region has been shown in BWS. This latter defect is associated with a higher risk of pediatric tumors, such as nephroblastoma. By contrast, LOM on the paternal allele at the telomeric ICR1 is observed in SRS. There is an abnormally high prevalence of conceptions by assisted reproductive technology (ART) among patients with BWS and SRS, suggesting that ART may favor imprinting alterations at the imprinted centromeric 11p15 locus (LOM at the maternally methylated ICR2 or LOM at the paternally methylated ICR1, respectively). The underlying cause of these imprinting defects (following ART or occurring spontaneously) remains unclear. However, recent data indicate that, in patients with BWS or SRS, including those born following ART for BWS, the methylation defect involves imprinted loci other than 11p15. Moreover, some patients exhibit LOM at both maternally and paternally methylated ICR, which suggests that unfaithful maintenance of DNA methylation marks following fertilization involves the dysregulation of a trans-acting regulatory factor.