Journal Article

Intergenerational epigenetic inheritance of cancer susceptibility in mammals

Page, David C, Bronson, Roderick T, Ebert, Benjamin L, Morgan, Elizabeth A, Lesch, Bluma J, Tothova, Zuzana, Liao, Zhicong

2019

Overview

Susceptibility to cancer is heritable, but much of this heritability remains unexplained. Some ‘missing’ heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. We report that deletion of the chromatin regulator Kdm6a (Utx) in the paternal germ line results in elevated tumor incidence in genetically wild type mice. This effect increases following passage through two successive generations of Kdm6a male germline deletion, but is lost following passage through a wild type germ line. The H3K27me3 mark is redistributed in sperm of Kdm6a mutants, and we define approximately 200 H3K27me3-marked regions that exhibit increased DNA methylation, both in sperm of Kdm6a mutants and in somatic tissue of progeny. Hypermethylated regions in enhancers may alter regulation of genes involved in cancer initiation or progression. Epigenetic changes in male gametes may therefore impact cancer susceptibility in adult offspring. Many diseases, such as certain cancers, run in families. Often, this is because several related individuals inherit a version of a gene that is faulty and causes the condition. But in a number of families with high rates of cancer, scientists are unable to pinpoint such disease-causing gene versions. Instead, it is possible that individuals inherit healthy genes that are not read and interpreted correctly by the cells. This could be because of epigenetic changes, modifications that do not alter the genetic code but can instead turn genes on or off temporarily by adding or removing certain marks on the genetic information. For a long time, researchers thought that epigenetic changes could not be passed from one generation to the next, but recent studies have revealed this is actually possible. However, it had never been shown that this could be associated with having a higher risk of developing cancer. Now, Lesch et al. show that epigenetic changes passed from male mice to their offspring make these animals more likely to develop tumors than typical mice. In the experiments, mouse sperm were genetically engineered to have a mutation in a gene called Kdm6a (also called Utx by cancer researchers), which controls the placement of epigenetic marks. Male mice carrying a defective Kdm6a gene were then mated to normal females. The resulting offspring developed more tumors than mice produced from normal sperm, even though they inherited a normal copy of the Kdm6a gene from their mother. Lesch et al. also show that the offspring have epigenetic marks similar to the ones found in the mutant sperm. This may change whether genes that stop or promote tumor formation are switched on or off. Certain cancer treatments work by targeting epigenetic changes. The results by Lesch et al. therefore call for more research into whether cancer patients exposed to these drugs could transmit these modifications if they have children soon after the end of their treatment. Ultimately, knowing more about how epigenetic changes are involved in inherited diseases may start to provide answers to families affected by cancer.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Cancer / Chromatin / Chromosomes and Gene Expression / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA methylation / Enhancers / Epigenesis, Genetic / Epigenetics / Females / Gametes / Gene expression / Gene regulation / Genetic diversity / Genetic engineering / Genetic Predisposition to Disease / Heredity / Heritability / Histone Demethylases - deficiency / histone modification / Leukemia / Males / Medicine / Mice / Mutation / Neoplasms - genetics / Principal components analysis / Sperm / spermatogenesis / Survival analysis / transgenerational inheritance / Tumors / Wills