Intergenerational epigenetic inheritance of cancer susceptibility in mammals
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 chromati...
| Main Authors: | , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications, Ltd
2020
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| Online Access: | https://hdl.handle.net/1721.1/125499 |
| _version_ | 1811086779888959488 |
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| author | Lesch, Bluma Page, David C |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Lesch, Bluma Page, David C |
| author_sort | Lesch, Bluma |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:34:37Z |
| format | Article |
| id | mit-1721.1/125499 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:34:37Z |
| publishDate | 2020 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1254992022-10-01T15:49:00Z Intergenerational epigenetic inheritance of cancer susceptibility in mammals Lesch, Bluma Page, David C Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology 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. National Cancer Institute (U.S.) (Cancer Center Support (core) Grant NIH 5 P30 CA06516) 2020-05-27T15:05:43Z 2020-05-27T15:05:43Z 2019-04 2020-01-15T18:08:52Z Article http://purl.org/eprint/type/JournalArticle 1534-4983 https://hdl.handle.net/1721.1/125499 Lesch, Bluma J. et al. “Intergenerational epigenetic inheritance of cancer susceptibility in mammals.” eLife 8 (2019): e39380 © 2019 The Author(s) en https://dx.doi.org/10.7554/ELIFE.39380 eLife Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | Lesch, Bluma Page, David C Intergenerational epigenetic inheritance of cancer susceptibility in mammals |
| title | Intergenerational epigenetic inheritance of cancer susceptibility in mammals |
| title_full | Intergenerational epigenetic inheritance of cancer susceptibility in mammals |
| title_fullStr | Intergenerational epigenetic inheritance of cancer susceptibility in mammals |
| title_full_unstemmed | Intergenerational epigenetic inheritance of cancer susceptibility in mammals |
| title_short | Intergenerational epigenetic inheritance of cancer susceptibility in mammals |
| title_sort | intergenerational epigenetic inheritance of cancer susceptibility in mammals |
| url | https://hdl.handle.net/1721.1/125499 |
| work_keys_str_mv | AT leschbluma intergenerationalepigeneticinheritanceofcancersusceptibilityinmammals AT pagedavidc intergenerationalepigeneticinheritanceofcancersusceptibilityinmammals |