Identification of Candidate Genes and Networks Associated with Developmental Competence in Oocytes and Cumulus Cells: A Cross Species Comparison of Gene Expression in Models of Increased and Decreased Competence.

Abstract

There are a number of aspects of infertility that are conserved across several species. In many mammalian species there is only a 25-35% chance of producing a live offspring after a single insemination, whether natural or artificial. Oocyte quality and developmental competence can be affected by a number of environmental factors such as nutrition and hormonal regulation. The objective of this study was to identify candidate genes expressed in mammalian oocytes and/or their cumulus cells which may be indicative of oocyte developmental competence. We performed a meta-analysis on previously published Affymetrix microarray data from various models of oocyte competence from several mammalian species (Bovine, Monkey, Mouse and Human), with the specific objective to identify candidate biomarkers of oocyte competence expressed in oocytes and or their cumulus cells. We identified 64 genes, 21 genes which were associated with increased competence including Mitd1, Kif12, and Gkap1. 43 genes were associated with decreased competence including Gdf9, Emi1, and one gene, Atrx, was linked to decreased competence in both oocytes and cumulus cells. Of the 64 genes identified, 5 (Hmga1, Foxm1, Map3k12, Tgfbr3, and Sfrp1) were identified by the Ingenuity Pathway Analysis-Biomarker program (http://www.ingenuity.com/products/ipa-biomarker.html) as being the most promising and relevant biomarker candidates. Only one of the genes identified by this program, Hmga1, was associated with increased competence. Hmga1 indirectly regulates the G2/M transition and is also involved in apoptosis, DNA binding, regulation of transcription and chromatin remodeling, which are key events in oocyte meiotic maturation. Additionally we carried out Bioinformatic analysis of the Affymetrix gene lists using Metacore from GeneGo (http://www.genego.com/metacore.php) to identified overpopulated networks. The regulation of Wnt signaling, mRNA processing and protein synthesis emerged as key networks associated with oocyte competence. We identified several transcription factors which regulate a large proportion of the differentially expressed transcripts in several of the competence models, which may themselves be reflective of the oocyte's competence. For example Nanog and Heat Shock Factor 1 were found to regulate 34 and 38 transcripts, respectively, which were associated with increased oocyte developmental competence. In conclusion we have identified a number of genes, pathways and regulatory networks which could potentially act as biomarkers of oocyte quality or as pharmacological targets for the improvement of in vitro embryo production systems. This work is funded by Science Foundation Ireland Grant # 07/SRC/B1156: Reproductive Biology Research Cluster. (platform)