Aging leads to DNA methylation alterations associated with loss of lineage fidelity and breast cancer in mammary luminal epithelial cells

DNA methylation in mammalian genomes is critical for repression of transposable elements (TEs) and regulation of transcription factor (TF) binding. Methylation loss in cancer cells results in widespread TE activation and altered TF binding that subsequently impact transcriptional networks. While the aging process is similarly characterized by changes to the methylome, the extent and its functional consequences have remained unclear. We report here that aging leads to distinct methylation changes in luminal epithelial cells, a key cell lineage implicated in age-related breast cancers. Regulatory elements and evolutionarily old TEs display consistent methylation changes at lineage-specific TF binding sites. Evolutionarily younger TEs, however, exhibit stochastic methylation loss that corresponds with increased methylation entropy. Each of these classes of methylation change impact the regulation of genes associated with luminal breast cancer. Altogether, our results indicate that aging leads to distinct DNA methylation changes that can rewire gene networks important for breast cancer. ### Competing Interest Statement The authors have declared no competing interest.