Vivian Carolyn J, Brinker Amanda E, Graw Stefan, Koestler Devin C, Legendre Christophe, Gooden Gerald C, Salhia Bodour, Welch Danny R
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
Heartland Center for Mitochondrial Medicine, Phoenix, Arizona.
Cancer Res. 2017 Nov 15;77(22):6202-6214. doi: 10.1158/0008-5472.CAN-17-1473. Epub 2017 Jun 29.
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. Because retrograde and anterograde communication exists 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. .
线粒体DNA（mtDNA）突变和多态性与包括癌症在内的许多复杂疾病有关。利用一种独特的小鼠模型，该模型包含来自一个小鼠品系的核DNA（nDNA）和来自不同小鼠品系的同质性线粒体单倍型——称为线粒体-核交换（MNX）——我们发现mtDNA可以改变乳腺肿瘤转移。由于核基因组和线粒体基因组之间存在逆向和顺向通讯，我们推测在核DNA（nDNA）表达和DNA甲基化方面存在由mtDNA驱动的差异变化。在配对的野生型和MNX小鼠的收获脑组织中测量全基因组nDNA甲基化和基因表达。在具有相同nDNA但不同mtDNA的品系之间观察到了选择性差异DNA甲基化和基因表达。这些观察结果为mtDNA如何改变表观遗传调控从而促进转移发病机制提供了见解。
