PgmNr M294: Genetic Variation Mediates the Epigenetic Response to Corticosteroids in Mice.

Authors:
Gregory W. Carter; Catrina Spruce; Robyn Ball; Wendy Pitman; Narayanan Raghupathy; Anna L. Tyler; Michael Walker; Kenneth Paigen; Petko M. Petkov


Institutes
The Jackson Laboratory, Bar Harbor, ME.


Abstract:

Epigenetic changes such as histone modifications and DNA methylation can modulate transcript expression through chromatin state reorganization. Natural genetic variation potentially alters these modifications, providing a molecular mechanism for many of the abundant cis-acting gene expression quantitative trait loci (eQTL) that associate local genetic variation with differences in transcript levels. Importantly, such variation may mediate the individual response to drug treatments. However, the effects of genetic variation on regulatory regions and the extent to which alterations in DNA methylation and local chromatin configuration play a role in them have not been extensively studied. We use purified hepatocytes from a set of nine diverse mouse strains, including the founders of the Collaborative Cross and DBA/2J, to study how genetic variation affects baseline epigenetic marks as well as the response to the glucocorticoid dexamethasone. By combining RNA-seq, bisulfite DNA-seq, and ChIP-seq assays for H3K4me1, H3K4me3, H3K27me3, and H3K27ac, we obtained a detailed view of the impact of genetic variation on both epigenetic marks and transcript abundances. We found that strain-specific variation in both gene expression and epigenetic marks is abundant, and is much greater than the consequences of dexamethasone treatment in terms of both number of loci affected and the magnitude of effects. Furthermore, the effect of treatment varies substantially across mouse strains, both at the genetic and epigenetic level, providing evidence of coordinated variation in molecular responses to a common immunosuppressant. Finally, our results provide insights on the extent to which local eQTL detected in mouse intercross populations such as the Diversity Outbred and BxD may be due to cis-acting genetic variation in promoter and enhancer activities.