Loss of epigenetic suppression of retrotransposons with oncogenic potential in aging mammary luminal epithelial cells
- Parijat Senapati1,6,
- Masaru Miyano2,
- Rosalyn W. Sayaman2,3,
- Mudaser Basam1,2,
- Amy Leung1,
- Mark A. LaBarge2,4,5 and
- Dustin E. Schones1,4
- 1Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, California 91010, USA;
- 2Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, California 91010, USA;
- 3Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143-0981, USA;
- 4Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, California 91010, USA;
- 5Center for Cancer Biomarker Research, University of Bergen, 5021 Bergen, Norway
Abstract
A primary function of DNA methylation in mammalian genomes is to repress transposable elements (TEs). The widespread methylation loss that is commonly observed in cancer cells results in the loss of epigenetic repression of TEs. The aging process is similarly characterized by changes to the methylome. However, the impact of these epigenomic alterations on TE silencing and the functional consequences of this have remained unclear. To assess the epigenetic regulation of TEs in aging, we profiled DNA methylation in human mammary luminal epithelial cells (LEps)—a key cell lineage implicated in age-related breast cancers—from younger and older women. We report here that several TE subfamilies function as regulatory elements in normal LEps, and a subset of these display consistent methylation changes with age. Methylation changes at these TEs occurred at lineage-specific transcription factor binding sites, consistent with loss of lineage specificity. Whereas TEs mainly showed methylation loss, CpG islands (CGIs) that are targets of the Polycomb repressive complex 2 (PRC2) show a gain of methylation in aging cells. Many TEs with methylation loss in aging LEps have evidence of regulatory activity in breast cancer samples. We furthermore show that methylation changes at TEs impact the regulation of genes associated with luminal breast cancers. These results indicate that aging leads to DNA methylation changes at TEs that undermine the maintenance of lineage specificity, potentially increasing susceptibility to breast cancer.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.277511.122.
-
Freely available online through the Genome Research Open Access option.
- Received November 15, 2022.
- Accepted June 23, 2023.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
