Genetics talks to epigenetics? The interplay between sequence variants and chromatin structure

Abstract

Transcription is regulated by two major mechanisms. On the one hand, changes in DNA sequence are responsible for genetic gene regulation. On the other hand, chromatin structure regulates gene activity at the epigenetic level. Given the fundamental participation of these mechanisms in transcriptional regulation of virtually any gene, they are likely to co-regulate a significant proportion of the genome. The simple concept behind this idea is that a mutation may have a significant impact on local chromatin structure by modifying DNA methylation patterns or histone type recruitment. Yet, the relevance of these interactions is poorly understood. Elucidating how genetic and epigenetic mechanisms co-participate in regulating transcription may assist in some of the unresolved cases of genetic variant-phenotype association. One example is loci that have biologically predictable functions but genotypes that fail to correlate with phenotype, particularly disease outcome. Conversely, a crosstalk between genetics and epigenetics may provide a mechanistic explanation for cases in which a convincing association between phenotype and a genetic variant has been established, but the latter does not lie in a promoter or protein coding sequence. Here, we review recently published data in the field and discuss their implications for genetic variant-phenotype association studies.

Keywords: Chromatin; DNA methylation; epigenetics; genetic variant; histone; single nucleotide polymorphism..

Fig. (1)

Schematic effects of GV on epigenetic marks. A, allele (a and b, respectively)-specific regulation of local DNA methylation states and examples of possible biological effects. Vertical lines mark GV position. Open and closed circles represent unmethylated and methylated residues, respectively. The b allele is hypothetically represented as the one associated with DNA hypermethylation spreading to adjacent sequences (arrows). B, normal expression patterns of two adjacent genes (left) are altered if a deletion in polyadenylation signal sequence of the upstream gene causes transcript extension to and silencing of a downstream gene (right). Closed circles on the right indicate hypermethylation of the overrun promoter of the downstream gene. C, long-range transcriptional impact of GV-associated epigenetic marks. The b allele is associated with enhancer-like histone marks (star) positioned in a chromatin loop extending to a gene promoter (white rectangle). D, noncoding SNP-containing transcripts (curved lines) regulate expression and epigenetic marks of different target genes (white boxes) depending on genotype. See [2,58,59,63,64,72] and text for details.

Fig. (2)

Simplified view of how dietary, environmental and possibly other exogenous factors can interfere with the establishment of allele-specific DNA methylation states and complicate comparisons between genetic association studies conducted in different populations. In population 1, those exogenous factors are weak or neutral and the b allele associates with local DNA hypermethylation compared to allele a (symbols are as in legend of Fig. 1). In population 2, exogenous factors (grey ovals) distinct in dose or type from the ones affecting population 1 override allele b-specific effects and lock both a and b alleles in a hypermethylated state. If b allele-associated and exogenous factor-induced epigenetic marks are comparable, genetic associations will be masked in population 2. For simplicity, DNA hypermethylation is represented as the effect of diet-related or environmental factors, but DNA hypomethylation is an equally likely outcome.