Abstract
Epigenetic mechanisms such as DNA methylation regulate genomic imprinting and account for the distinct non-equivalence of the parental genomes in the embryo. Chromosomal aneuploidy, a major cause of infertility, distorts this highly regulated disparity by the presence or absence of chromosomes. The implantation potential of monosomy embryos is negligible compared to their trisomy counterparts, yet the cause for this is unknown. This study investigated the impact of chromosomal aneuploidy on strict epigenetically regulated domains, specifically imprinting control regions present on aneuploid chromosomes. Donated cryopreserved human IVF blastocysts of transferable quality, including trisomy 15, trisomy 11, monosomy 15, monosomy 11, and donor oocyte control blastocysts were examined individually for DNA methylation profiles by bisulfite mutagenesis and sequencing analysis of two maternally methylated imprinting control regions (ICRs), SNRPN (15q11.2) and KCNQ1OT1 (11p15.5), and one paternally methylated imprinting control region, H19 (11p15.5). Imprinted genes within the regions were also evaluated for transcript abundance by RT-qPCR. Overall, statistically significant hypermethylated and hypomethylated ICRs were found in both the trisomy and monosomy blastocysts compared to controls, restricted only to the chromosome affected by the aneuploidy. Increased expression was observed for maternally-expressed imprinted genes in trisomy blastocysts, while a decreased expression was observed for both maternally- and paternally-expressed imprinted genes in monosomy blastocysts. This epigenetic dysregulation and altered monoallelic expression observed at imprinting control regions in aneuploid IVF embryos supports euploid embryo transfer during infertility treatments, and may specifically highlight an explanation for the compromised implantation potential in monosomy embryos.
Highlights
Embryonic chromosomal aneuploidy is a major cause of human infertility, and likely contributes to most failed conceptions, both natural and IVF
Our results indicate that the dysregulation of genomic imprinting in aneuploid blastocysts, the altered imprinted methylation leading to decreased gene expression observed in monosomy embryos, may contribute to their reduced implantation potential and support euploid embryo transfer following comprehensive chromosome screening in IVF cycles
Increased and decreased imprinting control regions (ICRs) methylation compared to controls contributed to altered imprinted gene expression
Summary
Embryonic chromosomal aneuploidy is a major cause of human infertility, and likely contributes to most failed conceptions, both natural and IVF. Monosomy errors involve the loss of one chromosome from a pair These embryos predominately do not implant, and rarely reach clinical pregnancy, having Turner Syndrome (XO) the only full monosomy that has the potential to develop to term. This significant disparity reported between pre- and post-implantation frequencies for monosomy embryos has recently been tallied, with 45.7% of preimplantation monosomies in blastocysts reduced to 6.3% of post-implantation monosomies in spontaneous abortuses [5]. The cause for this compromised implantation potential for monosomy embryos compared to their trisomy counterparts is unknown. An increasing number of aneuploidy studies have proposed a relationship between chromosome imbalance and epigenetics, though cause and consequence are still undetermined [6,7,8,9,10,11,12]
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