NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure

PLoS Genetics
Patrick J. MurphyKenneth I Aston

Abstract

Paternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. Here we use mouse models to investigate mechanisms and impacts of paternal CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking is associated with changes in prefrontal cortex DNAme and gene expression patterns in offspring. Remarkably, the epigenetic and transcriptional effects of CS exposure that we observed in wild type mice are partially recapitulated in Nrf2-/- mice and their offspring, independent of smoking status. Nrf2 is a central regulator of antioxidant gene transcription, and mice lacking Nrf2 consequently display elevated oxidative stress, suggesting that oxidative stress may underlie CS-induced heritable epigenetic changes. Importantly, paternal sperm DNAme changes do not overlap with DNAme changes measured in offspring prefrontal cortex, indicating that the observed DNAme changes in sperm are not directly inherited. Additionally, the changes in sperm DNAme associated with CS exposure were not observed in sperm of unexposed offspr...Continue Reading

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Methods Mentioned

BETA
RRBS
RNA-seq
RNAseq
Illumina sequencing
dissection
restriction digests
Hi-Seq

Software Mentioned

BedTool
USeq
DefinedRegionDifferentialSeq
GSEA
Deeptools
Gene Set Enrichment Analysis
SamTranscriptomeParser (
DAVID Functional Annotation Bioinformatics Resources
R
Bismark

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