Mechanisms controlling genomic imprinting and their dysregulation in human imprinting disorders

Imprinted genes play a pivotal role in regulating growth, development, and behavior through parent-of-origin-specific expression. This allelic specificity is orchestrated by "imprinting control regions" (ICRs), which depend on DNA methylation marks established on only one parental allele. The epigenetic life cycle of imprinting involves dynamic reprogramming: preexisting methylation is erased in primordial germ cells, followed by the establishment of new marks in either the female or male germline. After fertilization, these allele-specific methylation patterns are faithfully maintained throughout somatic development, ensuring proper gene dosage and function. Disruption of this tightly regulated epigenetic cycle, during germline erasure, establishment, or somatic maintenance, can lead to human diseases. Errors in imprinting are linked to at least thirteen congenital imprinting disorders, including Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). Endocrine dysfunctions are central to these conditions, reflecting the critical involvement of imprinted genes in growth regulation and hormonal signalling. In this review, we dissect the molecular mechanisms governing the reset, acquisition, maintenance, and transmission of imprints across development, and examine how perturbations at each stage contribute to the pathogenesis of imprinting disorders.