Characterization of the DNA Methylome and its Interindividual Variation in Human Peripheral Blood Monocytes

Abstract

Aim: Peripheral blood monocytes (PBMs) play multiple and critical roles in the immune response, and abnormalities in PBMs have been linked to a variety of human disorders. However, the DNA methylation landscape in PBMs is largely unknown. In this study, we characterized epigenome-wide DNA methylation profiles in purified PBMs. Materials & methods: PBMs were isolated from freshly collected peripheral blood from 18 unrelated healthy postmenopausal Caucasian females. Epigenome-wide DNA methylation profiles (the methylome) were characterized by using methylated DNA immunoprecipitation combined with high-throughput sequencing. Results: Distinct patterns were revealed at different genomic features. For instance, promoters were commonly (∼58%) found to be unmethylated; whereas protein coding regions were largely (∼84%) methylated. Although CpG-rich and -poor promoters showed distinct methylation patterns, interestingly, a negative correlation between promoter methylation levels and gene transcription levels was consistently observed across promoters with high to low CpG densities. Importantly, we observed substantial interindividual variation in DNA methylation across the individual PBM methylomes and the pattern of this interindividual variation varied between different genomic features, with highly variable regions enriched for repetitive DNA elements. Furthermore, we observed a modest but significant excess (p < 2.2 × 10^-16) of genes showing a negative correlation between interindividual promoter methylation and transcription levels. These significant genes were enriched in biological processes that are closely related to PBM functions, suggesting that alteration in DNA methylation is likely to be an important mechanism contributing to the interindividual variation in PBM function, and PBM-related phenotypic and disease-susceptibility variation in humans. Conclusion: This study represents a comprehensive analysis of the human PBM methylome and its interindividual variation. Our data provide a valuable resource for future epigenomic and multiomic studies, exploring biological and disease-related regulatory mechanisms in PBMs.

KEYWORDS::

• DNA methylation
• interindividual variation
• peripheral blood monocyte

Acknowledgements

The authors wish to thank M Gui at Arraystar Inc. (MD, USA) for his assistance in setting up and performing the methylated DNA immunoprecipitation coupled with the next-generation sequencing, and L Chavez at the Max-Planck-Institute for Molecular Genetics (Berlin, Germany) for providing consultation for data analysis.

Financial & competing interests disclosure

The investigators of this work were partially supported by grants from the NIH (P50AR055081, R01AG026564, R01AR050496, R01AR057049 and R03TW008221), the Franklin D Dickson/Missouri Endowment from University of Missouri-Kansas City, and the Edward G Schlieder Endowment from Tulane University. The work also benefited from the Shanghai Leading Academic Discipline Project (S30501). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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

The investigators of this work were partially supported by grants from the NIH (P50AR055081, R01AG026564, R01AR050496, R01AR057049 and R03TW008221), the Franklin D Dickson/Missouri Endowment from University of Missouri-Kansas City, and the Edward G Schlieder Endowment from Tulane University. The work also benefited from the Shanghai Leading Academic Discipline Project (S30501). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.