Chromatin variation associated with liver metabolism is mediated by transposable elements

Abstract

BackgroundFunctional regulatory regions in eukaryotic genomes are characterized by the disruption of nucleosomes leading to accessible chromatin. The modulation of chromatin accessibility is one of the key mediators of transcriptional regulation and variation in chromatin accessibility across individuals has been liked to complex traits and disease susceptibility. While mechanisms responsible for chromatin variation across individuals have been investigated, the overwhelming majority of chromatin variation remains unexplained. Furthermore, the processes through which the variation of chromatin accessibility contributes to phenotypic diversity remain poorly understood.\n\nResultsWe profiled chromatin accessibility in liver from seven strains of mice with phenotypic diversity in response to a high-fat/high-sucrose (HF/HS) diet and identified reproducible chromatin variation across the genome. We found that sites of variable chromatin accessibility were more likely to coincide with particular classes of transposable elements (TEs) than sites with common chromatin features. Evolutionarily younger long interspersed nuclear elements (LINEs) are particularly enriched for variable chromatin sites. These younger LINEs are enriched for binding sites of immune-associated transcription factors, whereas older LINEs are enriched for liver-specific transcription factors. Genomic region enrichment analysis indicates that variable chromatin sites at TEs contribute to liver metabolic pathways. Finally, we show that polymorphism of TEs and differential DNA methylation at TEs can both contribute to chromatin variation.\n\nConclusionsOur results demonstrate specific classes of TEs contribute to chromatin accessibility variation across strains of mice that display phenotypic diversity in response to a HF/HS diet. These results indicate that regulatory variation at TEs is an important contributor to phenotypic variation among populations.