Abstract
AimCharacterization of the hepatic epigenome following exposure to chemicals and therapeutic drugs provides novel insights into toxicological and pharmacological mechanisms, however appreciation of genome-wide inter- and intra-strain baseline epigenetic variation, particularly in under-characterized species such as the rat is limited.Material & methodsTo enhance the utility of epigenomic endpoints safety assessment, we map both DNA modifications (5-methyl-cytosine and 5-hydroxymethyl-cytosine) and enhancer related chromatin marks (H3K4me1 and H3K27ac) across multiple male and female rat livers for two important outbred laboratory rat strains (Sprague–Dawley and Wistar).Results & conclusionIntegration of DNA modification, enhancer chromatin marks and gene expression profiles reveals clear gender-specific chromatin states at genes which exhibit gender-specific transcription. Taken together this work provides a valuable baseline liver epigenome resource for rat strains that are commonly used in chemical and pharmaceutical safety assessment.
Highlights
Analysis of the global DNA modification patterns reveal that these cluster by strain before gender
A small number of promoter & genic DNA modification patterns differ between rat strains
These typically relate to genes with roles in a range of pathways including those associated with drug metabolic processes and cell surface receptor signalling pathways and may be relevant in explaining difference in toxicological responses between rat strains
Summary
Characterization of the hepatic epigenome following exposure to chemicals and therapeutic drugs provides novel insights into toxicological and pharmacological mechanisms, appreciation of genome-wide inter- and intra-strain baseline epigenetic variation, in under-characterized species such as the rat is limited
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