Читать книгу Genetic Disorders and the Fetus - Группа авторов - Страница 160

Epigenetic studies, such as analysis of genome‐wide DNA methylation, have aided our understanding of placental development and its unique nature.^{161, 162} Relative to somatic cells, the placenta exhibits global hypo‐methylation, although this is not distributed randomly but mainly in distinct blocks along the chromosomes referred to as “partially methylated domains.”¹⁶¹ There is striking hypo‐methylation of some repetitive elements and the inactive X chromosome promoters in females, whereas average methylation at autosomal gene promoters does not differ.^{163, 164} The distinct methylation of placental cells from somatic cells, such as blood, provides a means of distinguishing placental (fetal) from maternal cell‐free DNA in maternal blood for NIPT.

DNA methylation profiling can be used to characterize placental pathologies. For example, placentas associated with early‐onset PE exhibit widespread changes in DNA methylation.^{98, 165–169} A subset of these changes overlap sites altered in syncytial trophoblast differentiation and hypoxia exposure;¹⁶⁵ however, the relationship of the DNA methylation changes to the observed pathology is likely complex. Systematic changes in DNA methylation throughout gestation allow for methylation to be used as a gestational age “clock”.¹⁷⁰ While this clock is largely robust to placental pathology, placentas associated with PE show evidence of acceleration of this clock, consistent with the phenotype of advanced villous maturation. DNA methylation profiling of placentas at delivery is useful to distinguish among different etiologies underlying PE¹⁶⁹ and may be useful in the future development of new screening approaches.

Many imprinted DMRs are tightly maintained in placenta, and thus DNA methylation testing can be used for diagnosis of chromosomal imbalance in the placenta. For example, the parental origin of triploidy or the level of androgenetic cells in samples from placentas with PMD can be diagnosed from DNA methylation ratios at imprinting control regions.¹⁷¹ However, caution should be used in inferring imprinting defects in the fetus from evaluation of DNA methylation at imprinted DMRs in placenta. Some imprinted genes, such as CDKN1C and IGF2, have placental specific promoters,^{172, 173} and placental imprinted DMRs may differ from somatic ones for a given imprinted gene. Even for those that are maintained, some imprinting defects may arise post‐zygotically and the degree to which the placenta reflects imprinting status in the fetus has not been well established.

DNA methylation analysis is also typically used to evaluate X‐chromosome inactivation (XCI) skewing. It is important to note that XCI evaluation of the placenta cannot be used to infer skewed XCI in fetal tissues, as XCI occurs separately in these two lineages.¹⁷⁴ In addition, the inactive X chromosome is incompletely methylated in the placenta and there are extensive site‐to‐site differences in XCI status due to the clonal manner in which villous trees grow,^{174, 175} precluding use of a single site to infer XCI status of the placenta as a whole.