Chromosome Missegregation in Single Human Oocytes Is Related to the Age and Gene Expression Profile.

Stefano Barone,Maria Michela Pallotta,Cristiana Parri,Annalisa Frattini,Erika Rapalini,Roberto Valli,Antonio Musio,Abdul Waheed Khan,Gazzi Silvia,Patrizia Sarogni

doi:10.3390/ijms21061934

Abstract

The growing trend for women to postpone childbearing has resulted in a dramatic increase in the incidence of aneuploid pregnancies. Despite the importance to human reproductive health, the events precipitating female age-related meiotic errors are poorly understood. To gain new insight into the molecular basis of age-related chromosome missegregation in human oocytes, we combined the transcriptome profiles of twenty single oocytes (derived from females divided into two groups according to age <35 and ≥35 years) with their chromosome status obtained by array comparative genomic hybridization (aCGH). Furthermore, we compared the transcription profile of the single oocyte with the surrounding cumulus cells (CCs). RNA-seq data showed differences in gene expression between young and old oocytes. Dysregulated genes play a role in important biological processes such as gene transcription regulation, cytoskeleton organization, pathways related to RNA maturation and translation. The comparison of the transcription profile of the oocyte and the corresponding CCs highlighted the differential expression of genes belonging to the G protein-coupled receptor superfamily. Finally, we detected the loss of a X chromosome in two oocytes derived from women belonging to the ≥35 years age group. These aneuploidies may be caused by the detriment of REEP4, an endoplasmic reticulum protein, in women aged ≥35 years. Here we gained new insight into the complex regulatory circuit between the oocyte and the surrounding CCs and uncovered a new putative molecular basis of age-related chromosome missegregation in human oocytes.

Highlights

An oocyte’s competence is related to its ability to complete meiotic maturation, undergo fertilization and sustain embryonic development [1,2,3]
In order to determine the effect of oocyte age on the human transcriptome, we analyzed the gene expression profiles of 20 single oocytes derived from 20 women subdivided into two age groups:
In order to obtain new insight into the role of age in oocyte quality and the presence of meiotic error, we performed our analysis in fresh oocytes (MII derived from 20 women subdivided into two age groups)

Summary

Introduction

An oocyte’s competence is related to its ability to complete meiotic maturation, undergo fertilization and sustain embryonic development [1,2,3]. The complex relationship between oocyte, endocrine system and cumulus oophorus cell complex (COC) is postulated to be important for the acquisition of competence [4]. The oocyte releases, through gap junctions, growth factors that promote CC differentiation and proliferation, preventing their transition to mural granulosa cells [7,9]. In the context of assisted reproductive treatment (ART), this phenomenon poses a serious medical problem because chromosome missegregation and aneuploidy increase with age, leading to infertility and miscarriage [10,11,12,13]. Experimental data indicates that the aneuploidy rate in the oocytes of women under 25 years old is about 5%, 10–25% in the early 30 s and increases to 50% in women over 40 years [16,17,18,19]

Methods

Results

Conclusion