Normal mammary epithelia accumulate DNA methylation changes with age that are consistent with breast cancer methylomes

Abstract

<jats:p>The aging process is characterized by an accumulation of cellular damage, including alterations to the epigenome. While it is clear that DNA methylation patterns change with age, the mechanisms behind these epigenomic alterations - and their functional consequences - have remained unclear. One of the primary roles of DNA methylation in mammalian genomes is in the repression of retrotransposons. Many of these repetitive elements contain regulatory sequences, and loss of repression can lead to aberrant transcriptional regulation. Aging-associated DNA methylation loss at transposable elements (TEs), therefore, has the potential to rewire gene expression networks to be favorable for pathologies, including age-related diseases such as cancer. However, the extent of loss of epigenetic silencing at transposable elements during aging and the functional consequences of this have remained unclear. Luminal epithelial cells in the breast tissue are a key cell lineage implicated in age-related luminal breast cancers. We report here that aging leads to distinct DNA methylation patterns at tissue-specific regulatory elements and TEs in luminal epithelial cells. DNA methylation changes at regulatory elements are driven by altered activity of lineage-specific transcription factors such as ELF5 and TP63. However, transposable elements, especially recently evolved TEs, exhibit stochastic loss of methylation and increased methylation entropy with age. TEs that lose methylation with age regulate known breast cancer genes and are associated with elevated breast cancer risk. Altogether, our results indicate that aging leads to DNA methylation loss at evolutionarily young TEs that can impact gene networks important for age-related breast cancers.</jats:p>

Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

“…p < 0.005, adj. p < 0.1) and was highly enriched in DMRs that were hypomethylated in the older cells ( Figures S3Li-ii), supporting our earlier findings based on a more limited set of whole genome bisulfite sequencing (WGBS) data in LEPs [Senapati et al, 2020].…”

“…Hypomethylation of this CpG island region in older LEPs was confirmed in our WGBS dataset [Senapati et al, 2020] (Figure S7Hi). This 5-CpG DMR was located in the first intron ( Figure S7Hi), a region that has been shown to have inverse correlation between intron methylation and gene expression [Anastasiadi et al, 2018].…”

“…Schones. WGBS data were generated for LEPs from two younge <30y and two older >55y women for our other manuscript [Senapati, et al, 2020]. WGBS bigwig files were imported in the UCSC Genome Browser (GRCh37/hg19) and mapped to the CXXC5 gene region.…”

Epigenetic Clocks and Programmatic Aging

“…Epithelial tissue within the breast shows maturo-developmental plasticity that supports lactational function. It was recently reported that over the course of time during adulthood, the methylome of healthy proliferating breast epithelial tissues increasingly resembles that of breast cancer (Sayaman et al, 2022;Senapati et al, 2022). This is a potential example of a maturo-developmental process displaying AP.…”