Genome-wide DNA methylation analysis reveals hypomethylation in the low-CpG promoter regions in lymphoblastoid cell lines

Hum Genomics. 2017 May 12;11(1):8. doi: 10.1186/s40246-017-0106-6.


Background: Epidemiological studies of DNA methylation profiles may uncover the molecular mechanisms through which genetic and environmental factors contribute to the risk of multifactorial diseases. There are two types of commonly used DNA bioresources, peripheral blood cells (PBCs) and EBV-transformed lymphoblastoid cell lines (LCLs), which are available for genetic epidemiological studies. Therefore, to extend our knowledge of the difference in DNA methylation status between LCLs and PBCs is important in human population studies that use these DNA sources to elucidate the epigenetic risks for multifactorial diseases. We analyzed the methylation status of the autosomes for 192 and 92 DNA samples that were obtained from PBCs and LCLs, respectively, using a human methylation 450 K array. After excluding SNP-associated methylation sites and low-call sites, 400,240 sites were subjected to analysis using a generalized linear model with cell type, sex, and age as the independent variables.

Results: We found that the large proportion of sites showed lower methylation levels in LCLs compared with PBCs, which is consistent with previous reports. We also found that significantly different methylation sites tend to be located on the outside of the CpG island and in a region relatively far from the transcription start site. Additionally, we observed that the methylation change of the sites in the low-CpG promoter region was remarkable. Finally, it was shown that the correlation between the chronological age and ageing-associated methylation sites in ELOVL2 and FHL2 in the LCLs was weaker than that in the PBCs.

Conclusions: The methylation levels of highly methylated sites of the low-CpG-density promoters in PBCs decreased in the LCLs, suggesting that the methylation sites located in low-CpG-density promoters could be sensitive to demethylation in LCLs. Despite being generated from a single cell type, LCLs may not always be a proxy for DNA from PBCs in studies of epigenome-wide analysis attempting to elucidate the role of epigenetic change in disease risks.

Keywords: DNA methylation; Epigenetic epidemiology; Epigenome-wide analysis; Human methylation array; Lymphoblastoid cell lines.

MeSH terms

  • Acetyltransferases / genetics
  • Aging*
  • Blood Cells / metabolism
  • Cell Line, Transformed
  • CpG Islands*
  • DNA Methylation*
  • Fatty Acid Elongases
  • Genome-Wide Association Study*
  • Humans
  • LIM-Homeodomain Proteins / genetics
  • Lymphocyte Activation
  • Muscle Proteins / genetics
  • Transcription Factors / genetics


  • ELOVL2 protein, human
  • FHL2 protein, human
  • LIM-Homeodomain Proteins
  • Muscle Proteins
  • Transcription Factors
  • Acetyltransferases
  • Fatty Acid Elongases