Abstract
DNA methylation is a key epigenetic mechanism responsible for gene regulation, chromatin remodeling, and genome stability, playing a fundamental role during embryonic development. The aim of this study was to determine if these epigenetic marks are associated with chromosomal aneuploidy in human blastocysts. Surplus, cryopreserved blastocysts that were donated to research with IRB consent were chosen with varying chromosomal aneuploidies and respective implantation potential: monosomies and trisomies 7, 11, 15, 21, and 22. DNA methylation analysis was performed using the Illumina Infinium HumanMethylation450 BeadChip (~485,000 CpG sites). The methylation profiles of these human blastocysts were found to be similar across all samples, independent of chromosome constitution; however, more detailed examination identified significant hypomethylation in the chromosome involved in the monosomy. Real-time PCR was also performed to determine if downstream messenger RNA (mRNA) was affected for genes on the monosomy chromosome. Gene dysregulation was observed for monosomy blastocysts within significant regions of hypo-methylation (AVEN, CYFIP1, FAM189A1, MYO9A, ADM2, PACSIN2, PARVB, and PIWIL3) (P < 0.05). Additional analysis was performed to examine the gene expression profiles of associated methylation regulators including: DNA methyltransferases (DNMT1, DNMT3A, DNMT3B, DNMT3L), chromatin modifying regulators (CSNK1E, KDM1, PRKCA), and a post-translational modifier (PRMT5). Decreased RNA transcription was confirmed for each DNMT, and the regulators that impact DNMT activity, for only monosomy blastocysts (P < 0.05). In summary, monosomy blastocysts displayed hypomethylation for the chromosome involved in the error, as well as transcription alterations of associated developmental genes. Together, these modifications may be contributing to genetic instability and therefore be responsible for the limited implantation potential observed for full monosomy blastocysts.
Highlights
During reproduction, an embryo receives one set of chromosomes from the sperm, and one set from the oocyte, resulting in a complete set of 23 chromosome pairs
Gene dysregulation was observed for monosomy blastocysts within significant regions of hypo-methylation (AVEN, CYFIP1, FAM189A1, MYO9A, ADM2, PACSIN2, PARVB, and PIWIL3) (P < 0.05)
This study investigated the relationship between chromosome aneuploidy epigenetic mechanisms and gene transcription as possible mechanisms to explain the low implantation potential of monosomy embryos
Summary
An embryo receives one set of chromosomes from the sperm, and one set from the oocyte, resulting in a complete set of 23 chromosome pairs. Errors during meiotic or mitotic cell division can lead to extra or missing chromosomes, termed aneuploidy, which is the leading cause of miscarriage, stillbirth, and congenital birth defects [1]. Aneuploidy can occur for any chromosome with the highest proportion observed in conception belonging to the smaller sized chromosomes (15–22) [3]. Even the vast majority (>95%) of these trisomies will perish in utero. This is in contrast to full monosomies which almost never implant or result in an ongoing pregnancy. Partial fetal autosomal monosomies are observed during clinical pregnancy, where only a portion of a chromosome is missing, and these imbalances can lead to various phenotypes depending on the chromosome involved, the size of the absent chromosome, and which genes are impacted [5]
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