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. 2022 Jan 25;10(2):257.
doi: 10.3390/biomedicines10020257.

FAM111A Is a Novel Molecular Marker for Oocyte Aging

Huixia Yang  1 , Thomas Kolben  1 , Mirjana Kessler  1 , Sarah Meister  1 , Corinna Paul  1 , Julia van Dorp  1 , Sibel Eren  1 , Christina Kuhn  1   2 , Martina Rahmeh  1 , Cornelia Herbst  1 , Sabine Gabriele Fink  1 , Gabriele Weimer  1 , Sven Mahner  1 , Udo Jeschke  1   2 , Viktoria von Schönfeldt  1
Affiliations

FAM111A Is a Novel Molecular Marker for Oocyte Aging

Huixia Yang et al. Biomedicines. .

Abstract

Aging is the main cause of decline in oocyte quality, which can further trigger the failure of assisted reproductive technology (ART). Exploring age-related genes in oocytes is an important way to investigate the molecular mechanisms involved in oocyte aging. To provide novel insight into this field, we performed a pooled analysis of publicly available datasets, using the overlapping results of two statistical methods on two Gene Expression Omnibus (GEO) datasets. The methods utilized in the current study mainly include Spearman rank correlation, the Wilcoxon signed-rank test, t-tests, Venn diagrams, Gene Ontology (GO), Protein-Protein Interaction (PPI), Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and receiver operating characteristic (ROC) curve analysis. We identified hundreds of age-related genes across different gene expression datasets of in vitro maturation-metaphase II (IVM-MII) oocytes. Age-related genes in IVM-MII oocytes were involved in the biological processes of cellular metabolism, DNA replication, and histone modifications. Among these age-related genes, FAM111A expression presented a robust correlation with age, seen in the results of different statistical methods and different datasets. FAM111A is associated with the processes of chromosome segregation and cell cycle regulation. Thus, this enzyme is potentially an interesting novel marker for the aging of oocytes, and warrants further mechanistic study.

Keywords: DNA replication; FAM111A; WNT signaling pathway; cell cycle; cellular metabolism; histone modifications; oocyte aging.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Summary of the present study. (A) Groups included in the analysis of this study. (B) Flowchart of this study. GEO, Gene Expression Omnibus; IVF/ICSI, in vitro fertilization/intracytoplasmic sperm injection; IVM-MII, in vitro maturation-metaphase II; GV, germinal vesicle; IVO-MII, in vivo ovulation-metaphase II; N/A, not available; cor.test, Spearman rank correlation; GO, Gene Ontology; ROC, receiver operating characteristic; GSEA, Gene Set Enrichment Analysis; GSVA, Gene Set Variation Analysis; FAM111A, FAM111 Trypsin-Like Peptidase A.
Figure 2
Figure 2
Analysis of age-related genes. (A) Flowchart of the age-related analysis. (B) Overlapping results of cor.test and t-test for IVM-MII oocytes from Group I. (C) Overlapping results of cor.test and t-test for IVM-MII oocytes from Group II. (D) Overlapping results of age-related genes in Group I and Group II. (E) Based on the cor.test and t-test, FAM111A, IDI1, and LY6K are the statistically significant age-related genes in both Group I and Group II. IDI1, Isopentenyl-Diphosphate Delta Isomerase 1; LY6K, Lymphocyte Antigen 6 Family Member K. FC, fold change.
Figure 3
Figure 3
GO enrichment analysis of the age-related genes in IVM-MII oocytes from (A) Group I and (B) Group II. The age-related genes in this analysis were obtained from the overlapping cor.test and t-test results. The inner circle in the left figure indicates the Z-score value. The outer ring represents the significantly enriched terms, and the most upregulated and downregulated genes. The blue dot indicates the downregulated gene and the red dot indicates the upregulated gene. The right figure is the description of the enriched GO terms.
Figure 4
Figure 4
GO enrichment analysis of the overlapping age-related genes in IVM-MII oocytes from Group I and Group II. The age-related genes in this analysis were obtained from the overlapping results of cor.test in Group I and Group II. The x-axis represents the counts of the genes enriched in GO terms. The y-axis represents the significantly enriched terms in BP, CC, and MF. BP, biological process; CC, cellular component; MF, molecular function.
Figure 5
Figure 5
The capability of FAM111A for distinguishing young and old oocytes. The expression of FAM111A in the oocytes from young and old groups is visualized in (A) Group I and (B) Group II, and further validated in (C) Group III and (D) Group IV. The x-axis represents young and old oocytes. The y-axis represents FAM111A expression. p-values were calculated using a t-test or Wilcoxon signed-rank test. ROC curves are visualized in (E) Group I, (F) Group II, (G) Group III, and (H) Group Ⅳ. The x-axis of the ROC graph represents 1—specificity, and the y-axis represents sensitivity. AUC, area under the curve.
Figure 6
Figure 6
The PPI network and correlation analysis between FAM111A and its interacting protein partners. (A) The PPI network of FAM111A and its interacting protein partners. (B) Spearman gene-gene correlation matrix between FAM111A and its interacting partners. In the matrix, red and blue represent positive and negative correlations, respectively. The number in each square indicates the Spearman correlation coefficient (r-value). PPI, Protein–Protein Interaction.
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