Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression

Abstract

Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including cancer. Using a unique mouse model that contains nDNA from one mouse strain and homoplasmic mitochondrial haplotypes from different mouse strain(s) - designated Mitochondrial Nuclear Exchange (MNX) – we showed that mtDNA could alter mammary tumor metastasis. Since retrograde and anterograde communication exist between the nuclear and mitochondrial genomes, we hypothesized that there are differential mtDNA-driven changes in nuclear (n)DNA expression and DNA methylation. Genome-wide nDNA methylation and gene expression were measured in harvested brain tissue from paired wild-type and MNX mice. Selective differential DNA methylation and gene expression were observed between strains having identical nDNA, but different mtDNA. These observations provide insights into how mtDNA could be altering epigenetic regulation and thereby contribute to the pathogenesis of metastasis.

The Cytoplasm Affects the Epigenome in Drosophila melanogaster

“…The previously elusive molecular mechanisms uncovered here are likely candidates to mediate the documented mito-nuclear effects on the expression of health and life history traits such as longevity and reproductive success. Our findings support previous suggestions [9,12,[29][30][31][32]48] that epigenetic changes may be involved in the phenotypic effects of mito-nuclear interactions and provide a hypothesis as to why histone methylation was correlated to altered development in cattle embryos after mitochondrial replacement [29].…”

“…One study that is, however, broadly comparable to ours is a recent study in mice [32]. These authors examined differences in DNA methylation in individuals of strains with identical nuclear DNA but of different cytoplasms.…”

“…Both mitochondria and Wolbachia have been implicated to affect the nuclear epigenome [12,32,55]. While both could, therefore, be causing the differential H3K4me3 enrichment we observed, it is interesting to note that the only significantly enriched GO category we found was related to mitochondrial function.…”

“…After 8 generations of coevolution, these authors found differences in in hypo-or hypermethylation at several hundred loci. However, these authors [32] did not control for epigenetic changes caused by the nuclear transfer procedure itself.…”

“…Mitochondrial function is largely dependent on the nuclear genome, first and foremost due to the fact that the vast majority of proteins present in mitochondria are nuclear-encoded. However, studies have also shown or suggested that mitochondria can influence nuclear gene expression and might be involved in the epigenetic regulation of the nuclear genome [9,12,17,[28][29][30][31][32]. For instance, depleting mitochondria in cultured human kidney cells caused changes in nuclear DNA methylation, an important bearer of epigenetic information [33].…”