Gene variants influencing DNA methylation affect expression

The link between DNA sequences, DNA methylation and gene expression has been elucidated using a new technique that can detect the level of methylation at different points on the DNA.

Researchers based in Iceland have highlighted that, while methylation is understood to be a regulator of gene expression, methylation is dynamic and can be modified as a result of protein binding to DNA. As such, there could be other drivers behind the link between methylation and gene expression. Therefore, they looked at and compared three factors: methylation, gene expression and DNA sequence variation at different sites on the genome, using a new technique called nanopore sequencing.  

Authors from the biopharmaceutical company deCode genetics, based in Reykjavík, Iceland, which was behind the study wrote: 'Nanopore sequencing provides accurate detection of CpG methylation in DNA samples and has the benefit of achieving long sequences that facilitate phasing of the sequences to parental chromosomes to yield haplotype-resolved methylomes.'

Nanopore sequencing involves DNA molecules being drawn through tiny protein pores, and measurements of electric current being used to indicate which nucleotides in the DNA have passed through the pores. Chemical modifications of the nucleotides, such as methylation, can also be deduced from these same measurements.

Researchers looked specifically at methylated cytosines preceding guanine sequences in DNA, known as CpG sites, which tend not to exist in gene promotor or enhancer regions, which normally drive genetic expression. Lower levels of methylated CpG sites are associated with higher levels of gene expression.

In order to investigate the role DNA sequences have on methylation and thus gene expression, researchers measured DNA methylation of different haplotypes in 7179 whole-blood genomes.

They found that not only did sequence variants affect DNA methylation, further RNA sequencing data showed that variation in the DNA sequence drives most of the correlation found between gene expression and methylation. Results are published in Nature Genetics.

These findings open up the possibility of discovering how non-coding variants may contribute to disease development, the authors said. Most disease-linked variants are located in non-coding regions of the genome, making their impact challenging to understand.

The authors wrote: 'We expect nanopore sequencing of genomes from various cell types and tissues will be instrumental to investigating noncoding sequence variants of functional relevance.'