Association Between Sperm Mitochondrial DNA Copy Number and Nuclear DNA Methylation

Abstract

Aim: Accumulating evidence associates sperm mitochondria DNA copy number (mtDNAcn) with male infertility and reproductive success. However, the mechanism underlying mtDNAcn variation is largely unknown. Patients&methods: Sperm mtDNAcn and genome-wide DNA methylation were assessed using triplex probe-based quantitative PCR and Illumina’s 450K array, respectively. Multivariable models assessed the association between sperm mtDNAcn and DNA methylation profiles of 47 men seeking infertility treatment. Results: A priori candidate-gene approach showed sperm mtDNAcn was associated with 16 CpGs located at/near POLG and TWNK genes. Unbiased genome-wide analysis revealed that sperm mtDNAcn was associated with 218 sperm differentially methylated regions (q < 0.05), which displayed predominantly (94%) increases in methylation. Conclusion: Findings suggest that DNA methylation may play a role in regulating sperm mtDNAcn.

Keywords::

• copy number
• DNA methylation
• epigenetics
• infertility
• IVF
• mitochondria
• sperm

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2020-0253

author-contributions

OA Oluwayiose participated in data analysis and interpretation as well as drafting and revising of manuscript. S Josyula and E Houle participated in data analysis and interpretation and drafting of manuscript. C Marcho and BW Whitcomb participated in data analysis and interpretation and revision of manuscript. T Rahil and CK Sites participated in data acquisition and interpretation and revision of manuscript. JR Pilsner participated in conception and design, data acquisition and interpretation and revision of manuscript.

Financial&competing interests disclosure

This study was funded by the National Institutes of Health National Institute of Environmental Health Services (grant number R01-ES028298). The authors have no other relevant affiliations or financial involvement with any organization or entity, or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was funded by the National Institutes of Health National Institute of Environmental Health Services (grant number R01-ES028298). The authors have no other relevant affiliations or financial involvement with any organization or entity, or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.