Biology subjects

Basam, M.

Publications and source records attributed to Basam, M..

2 recordsLinked to original sources

bioRxiv2021

Mechanisms regulating interindividual epigenetic variability at transposable elements

Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.

genomics↗

bioRxiv2020

Aging leads to stochastic loss of silencing at transposons in mammary luminal epithelial cells

Luminal epithelial cells (LEps) are a key cell lineage implicated in age-related luminal breast cancers. Alterations to the epigenome are a hallmark of aging cells. However, the extent of age-associated DNA methylation alterations in LEps, and the corresponding functional consequences of these alterations, have remained unclear. We report here that aging leads to distinct methylation changes in LEps. Luminal lineage-specific genes gain promoter methylation, whereas myoepithelial-specific genes lose promoter methylation. Regulatory elements display methylation changes at lineage-specific TF binding sites consistent with the loss of lineage fidelity. CpG islands (CGIs) and transposable elements (TEs) have stochastic methylation gain and loss, respectively. PRC2 target genes that are hypermethylated in luminal breast cancer exhibit stochastic methylation increase with age. TEs with stochastic methylation loss are activated in breast cancer and potentially function as regulatory elements contributing to the loss of lineage fidelity with age. Each of these classes of methylation changes impact the regulation of genes associated with luminal breast cancer. Altogether, our results indicate that aging leads to DNA methylation changes that could determine breast cancer susceptibility. SignificanceMammary luminal epithelial cells lose lineage-specific expression with age and accumulate stochastic methylation changes that lead to loss of silencing at transposable elements. These age-dependent events potentially promote breast cancer susceptibility.

genomics↗