Single Nucleotide Resolution Analysis Reveals Pervasive, Long-Lasting DNA Methylation Changes by Developmental Exposure to a Mitochondrial Toxicant.

Lozoya, Oswaldo A; Xu, Fuhua; Grenet, Dagoberto; Wang, Tianyuan; Grimm, Sara A; Godfrey, Veronica; Waidyanatha, Suramya; Woychik, Richard P; Santos, Janine H

Mitochondrial-driven alterations of the epigenome have been reported, but whether they are relevant at the organismal level remains unknown. The viable yellow agouti mouse (Avy) is a powerful epigenetic biosensor model that reports on the DNA methylation status of the Avy locus, which is established prior to the three-germ-layer separation, through the coat color of the animals. Here we show that maternal exposure to rotenone, a potent mitochondrial complex I inhibitor, not only changes the DNA methylation status of the Avy locus in the skin but broadly affects the liver DNA methylome of the offspring. These effects are accompanied by altered gene expression programs that persist throughout life, and which associate with impairment of antioxidant activity and mitochondrial function in aged animals. These pervasive and lasting genomic effects suggest a putative role for mitochondria in regulating life-long gene expression programs through developmental nuclear epigenetic remodeling.