dos Santos Ferreira, C. | bioRxiv Science

bioRxiv2022

A Sexual Bias in mitochondrial protein-coding gene expression across different tissues and the prognostic value in multiple cancers

Mitochondria in mammalian cells provide ATP through oxidative phosphorylation. The overproduction of reactive oxygen species (ROS) in mitochondrial cells promotes cancer by modifying gene expression or function. Mating introduces competing mitochondrial (mtDNA) and nuclear DNA (nDNA) gene products, leading to biological differences between males and females for diseases and disorders such as cancer. There is a significant sex bias in aging-related conditions. We aimed to investigate whether sex and age affect mitochondrial protein-coding gene expression in cancer and, if so, to determine the prognosis value in survival outcomes, stemness, and immune cell infiltrates. We compared normal versus primary tumor transcriptomes (bulk RNA-Seq) from The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) projects to test these hypotheses. Correlations between gene expression, survival, protective or risk factor, stemness, and immune cell infiltrate were performed in RStudio using UCSC Xena Shiny. Eleven mitochondrial protein-coding genes were altered in brain cancer (MT-ND2, MT-ND1, MT-ATP8, MT-ATP6, MT-CO2, MT-CYB, MT-CO3, MT-ND4L, MT-ND4, MT-ND3, MT-CO1). MT-ND5 and MT-ND6 are disproportionately expressed in female brain tissues. Mitochondrial global polymorphic expression sites of variation were more significant in the 50-59 and 60-79-year-old age groups than in the 20-49-year-old age groups. Pan-cancer survival analysis revealed a 4-component gene signature (MT-CO1, MT-CO2, MT-ND5, and MT-ND6) downregulated in low-grade glioma (LGG). This gene signature increased LGG overall survival, disease-specific survival, and progression-free interval without sex-specific association. However, the correlation with disease-free interval survival was female-specific. The 4-component gene signature was protective in LGG but risky in thymoma cancer and uterine corpus endometrial carcinoma. In LGG, the 4-component gene signature positively correlated with immune monocyte, NK, and B cell infiltrates and negatively correlated with T cell CD4+ Th2, macrophage M1 and M2, myeloid dendritic cell, and neutrophil. We identified a 13-component mitochondrial protein-coding gene signature associated with stemness in kidney chromophobe. A sex-biased effect was observed in mitochondrial protein-coding for brain tissues, with a female bias. However, an aging effect with higher polymorphic site expression was observed in male tissues. We conclude that the differentially expressed mitochondrial protein-coding genes provide new insights into carcinogenesis, helping to identify new prognostic markers. The overexpression of the 4-component gene signature is associated with a better prognosis in LGG, with positive and negative correlations with immune cell infiltrates.

genomics↗

bioRxiv2019

A Differentially Methylated CpG Site in the IL4 Gene Associated with Anti-FVIII Inhibitor Antibody Development in Hemophilia A

Hemophilia A is the most common clotting disorder in humans. It affects one in five thousand live-born children. Mutations in the X-chromosome linked F8 gene lead to the deficiency of circulating factor VIII (FVIII). The defect is characterized by severe bleeding. The standard therapy is to replace the deficient factor intravenously. The main adverse event of the therapy is the development of anti-FVIII inhibitor antibodies that impair coagulation and result in increased complications and risk of death. Several risk factors have been described for the development of inhibitor antibodies, among them age, type of FVIII administered, ethnicity, and variant alleles in immune response genes. Epigenetic risks factors have not yet been explored. This work aimed to evaluate the methylation statuses at thirteen CpG sites (5meCpG) in regulatory regions of the IL1B, IL2, IL4, IL6, IL10, TNF, IFNG, CTLA4, CD28, and CST7 immune regulation genes in hemophilia A affected males on replacement therapy who develop or do not develop inhibitor antibodies. At each of the thirteen specific CpG sites, we observed one of three possible statuses: hypermethylated, hypomethylated or intermediate methylated. We found a statistically significant (p = 0.04) decrease in the methylation level at one CpG site in the IL4 intron 1 (CpG-3) in the affected group of patients presenting with anti-FVIII inhibitors as compared with the group of patients without inhibitors. The differential 5meCpG-3 maps within a predicted enhancer region in IL4 intron 1 that overlaps DNase I hypersensitive chromatin region of the Th2 IL5, IL13, and IL4 cytokine gene cluster and, therefore, permissive for gene expression. Six-bp upstream of the differentially 5meCpG-3 is the rs2227282 cis expression quantitative trait locus that influences the transcript levels of the PDLIM4, SLC22A4, SLC22A5, RAD50, IL4, KIF3A, SEPT8 genes. We consider the IL4 (CpG-3) site a promising lead epigenetic mark, the potential value of which must be appraised in a larger group of patients. The methodology employed also allowed to evaluate the distribution of the IL6 rs35081782 insertion/deletion variant, associated with white blood cell count traits in genome-wide association studies, and which showed no difference in distribution between the groups of patients.

genetics↗