Genetic and epigenetic determinants of inter-individual variability in responses to toxicants

Abstract

It is well established that genetic variability has a major impact on susceptibility to common diseases, responses to drugs and toxicants, and influences disease-related outcomes. The appreciation that epigenetic marks also vary across the population is growing with more data becoming available from studies in humans and model organisms. In addition, the links between genetic variability, toxicity outcomes and epigenetics are being actively explored. Recent studies demonstrate that gene-by-environment interactions involve both chromatin states and transcriptional regulation, and that epigenetics provides important mechanistic clues to connect expression-related quantitative trait loci (QTL) and disease outcomes. However, studies of Gene×Environment×Epigenetics further extend the complexity of the experimental designs and create a challenge for selecting the most informative epigenetic readouts that can be feasibly performed to interrogate multiple individuals, exposures, tissue types and toxicity phenotypes. We propose that among the many possible epigenetic experimental methodologies, assessment of chromatin accessibility coupled with total RNA levels provides a cost-effective and comprehensive option to sufficiently characterize the complexity of epigenetic and regulatory activity in the context of understanding the inter-individual variability in responses to toxicants.

Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion

“…The mapping of mouse strain–selective pertubations of cis -acting regulatory elements (cistrome) provides novel TF–based insights into the molecular basis for susceptibility to PB-induced rodent liver tumor promotion (Fig 5E). These observations are also consistent with recently reported links between genetic variation and tissue-specific epigenetic perturbations after toxicant exposures (Lewis et al, 2017; Israel et al, 2018). Thus, the integration of genetic, epigenomic, and transcriptomic data together with phenotypic endpoints has the potential to enhance mechanism-based safety assessment of both chemicals and pharmaceuticals.…”

“…The epigenomic landscape is strongly responsive to environmental conditions, including exposure to xenobiotics such as chemicals and pharmaceuticals (Jirtle & Skinner, 2007; Feil & Fraga, 2012) and, thus, represents an important molecular space for gaining potential insight into pharmacologic and toxicologic responses to xenobiotics (Szyf, 2007; Lewis et al, 2017; Israel et al, 2018). This study highlights the functional and toxicological relevance of hepatic epigenomic responses in a well-characterized rodent model for drug-induced non-genotoxic carcinogenesis.…”

Tissue- and strain-specific effects of a genotoxic carcinogen 1,3-butadiene on chromatin and transcription

“…Extending the complexity of the experimental designs of Gene × Environment investigations to the Epigenome may uncover not only relationships between chemical exposures and gene expression, but also determine the regulatory mechanisms altered by exposures; however, the complexity and technical challenges make such studies difficult (Lewis et al 2017). Our recent study examined effects of 1,3-butadiene on DNA damage, messenger RNA and microRNA expression, and genome-wide chromatin accessibility in the lung in the same C57BL/6J and CAST/EiJ mouse strains (Chappell et al 2017).…”

“…We focused on three readouts that allow for explorations of the relationships between epigenetic and transcriptional activity in the context of inter-individual variability in responses to toxicants: RNA-seq to comprehensively quantify multiple types of RNA transcripts, ATAC-seq to identify “accessible chromatin”, and ChIP-seq for H3K27ac to characterize regions that are active for transcription. We posit that this combination of assays represents a cost-effective and comprehensive approach that enables assessment of chromatin accessibility coupled with various RNA levels to comprehensively characterize epigenetic and transcriptional activity in the context of inter-individual variability in responses to a toxicant (Lewis et al 2017).…”

“…In order to evaluate population epigenomic variability, informative assays and endpoints need to be incorporated into both toxicology and epigenetic studies. RNA-seq in conjunction with ATAC-seq represents a cost-effective method to sufficiently investigate the link between genetic variants and epigenetic landscape in the inter-individual responses to toxicant exposure (Lewis et al 2017). This combination of techniques provides the opportunity to identify and resolve regions of active or repressed enhancers and promoters.…”