Interindividual variability and co-regulation of DNA methylation differ among blood cell populations

Abstract

DNA methylation regulates gene expression in a cell-type specific way. Although peripheral blood mononuclear cells (PBMCs) comprise a heterogeneous cell population, most studies of DNA methylation in blood are performed on total mononuclear cells. In this study, we investigated high resolution methylation profiles of 58 CpG sites dispersed over eight immune response genes in multiple purified blood cells from healthy adults and newborns. Adjacent CpG sites showed methylation levels that were increasingly correlated in adult blood vs. cord blood. Thus, while interindividual variability increases from newborn to adult blood, the underlying methylation changes may not be merely stochastic, but seem to be orchestrated as clusters of adjacent CpG sites. Multiple linear regression analysis showed that interindividual methylation variability was influenced by distance of average methylation levels to the closest border (0 or 100%), presence of transcription factor binding sites, CpG conservation across species and age. Furthermore, CD4+ and CD14+ cell types were negative predictors of methylation variability. Concerns that PBMC methylation differences may be confounded by variations in blood cell composition were justified for CpG sites with large methylation differences across cell types, such as in the IFN-γ gene promoter. Taken together, our data suggest that unsorted mononuclear cells are reasonable surrogates of CD8+ and, to a lesser extent, CD4+ T cell methylation in adult peripheral, but not in neonatal, cord blood.

Keywords: :

• DNA methylation
• interindividual variability
• immune response genes
• cord blood
• peripheral blood

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest are disclosed.

Acknowledgments

We thank the staff of the Clinical and Epidemiological Investigation Center (CIEC, CRP-Santé) for recruitment of participants and the Dr. Bohler Hospital personnel for collaboration and sample collection. We also thank Oliver Hunewald for support with bioinformatics analysis and Sophie Mériaux for technical help. This work was supported by the Centre de Recherche Public de la Santé (CRP-Santé) and the Ministry of Higher Education and Research of Luxembourg.

Supplemental Materials

Supplemental materials may be found here: www.landesbioscience.com/journals/epigenetics/article/22845