Lessons from imprinted multilocus loss of methylation in human syndromes: A step toward understanding the mechanisms underlying these complex diseases

Abstract

Genomic imprinting is one of the most important epigenetic mechanisms of regulation. Faithful establishment and maintenance of imprinting during mammalian fetal development is crucial for correct fetal and postnatal development of the individual. In humans, numerous complex syndromes (including Russell Silver Syndrome and Beckwith Wiedemann syndrome) and cancers are associated with loss of imprinting (LOI) at particular loci. Over recent years, there has been increasing evidence that LOI is not only an isolated event occurring at a given locus involved in a particular syndrome, but that many patients with a given syndrome have multilocus imprinting defects affecting both parental alleles. This new evidence demonstrates that these anomalies occur during the post-fertilization period of fetal development and raises the question of what mechanisms lead to these multilocus imprinting defects. Identification of the factors involved in the maintenance and/or the establishment of imprinting is undoubtedly crucial for understanding both the mechanisms underlying imprinting regulation and which disruptions lead to these complex diseases.