Epigenetics of Gestational Trophoblastic Disease: Genomic Imprinting and X Chromosome Inactivation

摘要

Genomic imprinting, the selective suppression of one of the two parental alleles of various genes, has been proposed to play an important regulatory role in the development of the placenta of eutherian mammals. The "parental conflict hypothesis" views that parents of opposite sex have conflicting interests in allocating resources to their offspring by the mother, proposing that growth-promoting genes are mainly expressed from the paternally inherited genome and are silent in the maternally inherited counterparts. X chromosome inactivation plays a central role in compensating for the double dose of X-linked genes in cells of the female relative to cells of the male.In the placenta of some species, X inactivation represents a special form of epigenetic imprinting. The paternal X chromosome is preferentially imprinted and silent in mouse trophectoderm, a tissue type from which gestational trophoblastic diseases arise. Growing body of evidence has suggested that the pathogenesis of gestational trophoblastic diseases involves altered genomic imprinting. Abnormal expressions of imprinted genes, such as IGF2 and H19, have been implied in the development of molar pregnancies and gestational choriocarcinoma. Moreover, unique genetic modes have long been established in hydatidiform moles: all complete moles have diandric diploid or tetraploid paternal-only genome and partial moles have triploid diandric and monogynic genome. Consistent with parental imprinting theory, partial mole occurs only with diandroid but digynic troploidy. Recent studies have found that all human placental site trophoblastic tumors arose from a female conceptus, suggesting that a functional paternal X chromosome is important for the neoplastic transformation, likely through inappropriate expression of paternal X-linked genes.