title: [Epigenetics, genomic imprinting and developmental disorders].
abstract: Epigenetic phenomena play a key role in regulating gene expression. One of the most widely studied epigenetic modification is DNA methylation at cytosine residues of CpG dinucleotides in gene promoters, transposons and imprinting control regions (ICR). Genomic imprinting refers to epigenetic marking of genes that results in monoallelic expression depending on the parental origin. Several genes encoding key hormones involved in embryonic and fetal growth are imprinted. There are two critical periods of 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 gender. Upon fertilization, genome-wide demethylation is followed by a wave of de novo methylation, both processes being resisted by imprinted loci. Disruption of imprinting can cause growth defects such as the Beckwith-Wiedemann overgrowth syndrome (BWS) and the Russell-Silver (RSS) intrauterine and postnatal growth retardation syndrome. These growth disorders are caused by abnormal DNA methylation in the 11p15 imprinted region encompassing many imprinted genes, such as IGF2. BWS has been linked to loss of methylation (LOM) in the centromeric ICR2/KCNQIOT1 region of the maternal allele, or gain of methylation in the telomeric ICR1/IGF2/H19 region of the maternal allele. This latter epigenetic defect is associated with an increased risk of tumors such as nephroblastoma. LOM in the telomeric ICR1 region of the paternal allele has been detected in RSS. Early embryogenesis is a critical period of epigenetic regulation, and is sensitive to environmental factors. Individuals conceived with the help of assisted reproductive technology (ART) are over-represented among BWS patients, suggesting that ART may favor altered imprinting at the imprinted centromeric 11p15 locus (LOM in the maternally methylated ICR2 region). The underlying cause of these imprinting defects, both spontaneous and ART-related, is unclear. However, recent data show that, in patients with BWS or RSS, including those conceived with the help of ART the DNA methylation defect involves imprinted loci other than 11p15. This suggests that unfaithful maintenance of DNA methylation marks following fertilization involves dysregulation of a trans-acting regulatory factor.
authors.affiliation: UPMC ParisVI-INSERM UMRS.938, Paris, France. yves.lebouc@trs.aphp.fr
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rossignol
authors.forename: Salah
authors.initials: S
authors.lastname: Azzi
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brioude
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cabrol
authors.forename: Christine
authors.initials: C
authors.lastname: Gicquel
authors.forename: Irène
authors.initials: I
authors.lastname: Netchine
mesh_terms: D000013:Congenital Abnormalities / Q000235:genetics*; D019175:DNA Methylation; D057890:Epigenomics; D018392:Genomic Imprinting; D006801:Humans