Intergenerational epigenetic inheritance of cancer susceptibility in mammals
Name
elife-39380-v1.pdf
Description
Published version
Size
7.4 MB
Format
Adobe PDF
Checksum (MD5)
6c7853d66c5148a497bac53fc2c3b421
Author(s)
Lesch, Bluma
Page, David C
Date Issued
April 2019
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Lesch, Bluma J. et al. “Intergenerational epigenetic inheritance of cancer susceptibility in mammals.” eLife 8 (2019): e39380 © 2019 The Author(s)
Version
Final published version
Abstract
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.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.7554/ELIFE.39380
