Natural variation of histone modification and its impact on gene expression in rat. Natural variation of histone modification and its impact on gene expression in rat

Histone modifications are epigenetic marks that play fundamental roles in many biological processes including the control of chromatin-mediated regulation of gene expression. To begin to understand the impact of natural variation on histone methylation levels we generated and quantified large-scale genome-wide ChIP-seq data in a panel of rat recombinant inbred strains and their parental progenitors. Linkage analysis identified hundreds of cis- and trans-acting loci responsible for quantitative differences in histone trimethyl-lysine levels in left ventricular heart and liver tissues. We assessed the association of histone methylation and gene expression levels by generating deep RNA-seq profiles across the segregating population. Among the main findings, causal modelling of DNA variation together with histone methylation and gene expression levels enhanced the prediction of gene expression traits (eQTLs) by ~20%. Moreover, allele specific differences of histone trimethyl-lysine levels at alternative promoters were associated with differential usage of transcriptional start sites. Our data suggest that genetic variation has widespread impact on histone modifications. The highly adapted interplay between DNA variation and chromatin structure has consequences on gene and isoform expression as direct functional outcome and demonstrated new avenues to find novel genotype phenotype relationships.