Abstract
The presence of an extra chromosome in the embryo karyotype often dramatically affects the fate of pregnancy. Trisomy 16 is the most common aneuploidy in first-trimester miscarriages. The present study identified changes in DNA methylation in chorionic villi of miscarriages with trisomy 16. Ninety-seven differentially methylated sites in 91 genes were identified (false discovery rate (FDR) < 0.05 and Δβ > 0.15) using DNA methylation arrays. Most of the differentially methylated genes encoded secreted proteins, signaling peptides, and receptors with disulfide bonds. Subsequent analysis using targeted bisulfite massive parallel sequencing showed hypermethylation of the promoters of specific genes in miscarriages with trisomy 16 but not miscarriages with other aneuploidies. Some of the genes were responsible for the development of the placenta and embryo (GATA3-AS1, TRPV6, SCL13A4, and CALCB) and the formation of the mitotic spindle (ANKRD53). Hypermethylation of GATA3-AS1 was associated with reduced expression of GATA3 protein in chorionic villi of miscarriages with trisomy 16. Aberrant hypermethylation of genes may lead to a decrease in expression, impaired trophoblast differentiation and invasion, mitotic disorders, chromosomal mosaicism and karyotype self-correction via trisomy rescue mechanisms.
Highlights
The presence of an extra chromosome in the embryo karyotype often dramatically affects the fate of pregnancy
Miscarriages with a normal karyotype and trisomy on other chromosomes were included in the study at this point because we were interested in the specificity of identified differential methylation of these genes for trisomy 16
One previous study examined the methylation profile in fetuses with trisomy 16 in the first and third trimesters of pregnancy, in which disturbances of placental DNA methylation in the third trimester and the association of aberrant methylation of certain genes with early-onset preeclampsia were studied in detail[9]
Summary
The presence of an extra chromosome in the embryo karyotype often dramatically affects the fate of pregnancy. Aberrant hypermethylation of genes may lead to a decrease in expression, impaired trophoblast differentiation and invasion, mitotic disorders, chromosomal mosaicism and karyotype self-correction via trisomy rescue mechanisms. Miscarriages with trisomy 16 have abnormal chorionic villous morphology with a cystic, clubbed, or hypoplastic appearance Mosaic forms of this aneuploidy occur later in pregnancy and postnatally in rare cases[5]. Mosaic forms of trisomy 16 are associated with a high probability of fetal death, preterm birth, intrauterine growth retardation, fetal abnormalities, and preeclampsia[6] These malformations likely occur due to the aberrant expression of imprinted genes located on chromosome 167,8. Data on DNA methylation in trisomy 16 in the first trimester of pregnancy, during which there is active placental differentiation and invasion of endovascular cytotrophoblasts into the spiral arteries, are scarce
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