CpG Island Methylation in Human Lymphocytes Is Highly Correlated with DNA Sequence, Repeats, and Predicted DNA Structure

Abstract

CpG island methylation plays an important role in epigenetic gene control during mammalian development and is frequently altered in disease situations such as cancer. The majority of CpG islands is normally unmethylated, but a sizeable fraction is prone to become methylated in various cell types and pathological situations. The goal of this study is to show that a computational epigenetics approach can discriminate between CpG islands that are prone to methylation from those that remain unmethylated. We develop a bioinformatics scoring and prediction method on the basis of a set of 1,184 DNA attributes, which refer to sequence, repeats, predicted structure, CpG islands, genes, predicted binding sites, conservation, and single nucleotide polymorphisms. These attributes are scored on 132 CpG islands across the entire human Chromosome 21, whose methylation status was previously established for normal human lymphocytes. Our results show that three groups of DNA attributes, namely certain sequence patterns, specific DNA repeats, and a particular DNA structure, are each highly correlated with CpG island methylation (correlation coefficients of 0.64, 0.66, and 0.49, respectively). We predicted, and subsequently experimentally examined 12 CpG islands from human Chromosome 21 with unknown methylation patterns and found more than 90% of our predictions to be correct. In addition, we applied our prediction method to analyzing Human Epigenome Project methylation data on human Chromosome 6 and again observed high prediction accuracy. In summary, our results suggest that DNA composition of CpG islands (sequence, repeats, and structure) plays a significant role in predisposing CpG islands for DNA methylation. This finding may have a strong impact on our understanding of changes in CpG island methylation in development and disease.

Methylation of Human MicroRNA Genes in Normal and Neoplastic Cells

“…A role of DNA attributes in predisposing CpG islands to DNA methylation has been shown recently. 37 Alternatively, miRNA genes might also be embedded in specific chromatin structures that predispose them to DNA methylation.…”

Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

“…Alternative promoters of SLC12A6 were computationally analyzed using the BIMAS promoter scan software (BIMAS promoter scan; http://www-bimas.cit.nih.gov/molbio/proscan), and by comparison with recent predictive annotation of default epigenetic states and predicted DNA methylation of all human CpG islands (Bock et al, 2006(Bock et al, , 2007. Predictions were obtained from http://rd.plos.org/10.1371_journal.pcbi.…”

GC skew defines distinct RNA polymerase pause sites in CpG island promoters

“…As a result, there is an inverse relationship between DNA methylation and H3K4 methylation, with unmethylated CGI domains uniquely marked by H3K4me3 genome-wide. DNA sequence features have also been reported to promote or to prevent DNA methylation at CGIs (Feltus et al 2003;Bock et al 2006;Ginno et al 2012). How chromatin structure and DNA sequence converge to regulate transcription initiation and elongation at CGIs is not well understood.…”