Search

The normal adult human mammary gland is a continuous bilayered epithelial system. Bipotent and myoepithelial progenitors are prominent and unique components of the outer (basal) layer. The inner (luminal) layer includes both luminal-restricted progenitors and a phenotypically separable fraction that lacks progenitor activity. We now report an epigenomic comparison of these three subsets with one another, with their associated stromal cells, and with three immortalized, non-tumorigenic human mammary cell lines. Each genome-wide analysis contains profiles for six histone marks, methylated DNA, and RNA transcripts. Analysis of these datasets shows that each cell type has unique features, primarily within genomic regulatory regions, and that the cell lines group together. Analyses of the promoter and enhancer profiles place the luminal progenitors in between the basal cells and the non-progenitor luminal subset. Integrative analysis reveals networks of subset-specific transcription factors., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells.

Interplay between the genome and the epigenome is fundamental to cell type functionality and the mechanisms of associated diseases. Most studies that have explored these interactions have leveraged population-scale genotype surveys to associate genetic polymorphisms with epigenetic states in whole blood or other heterogenous tissue types. Epigenetic states differ by cell type, raising the possibly of cell-type-specific genetic-to-epigenetic relationships that could drive specific functional states and disease predisposition. To address this, I mapped the epigenetic impact of genomic variants across a cohort of eight individuals in four distinct cell types of the human breast by searching for variant alleles strongly associated with histone modification peaks. I found that peak-associated variants were relatively enriched in active histone modification landscapes, drove allele-specific recruitment of active histone modifications, and disproportionately predicted transcription factor binding site creation/disruption events of transcription factors upregulated in the same cell type. Correlation with nearest-gene transcription allowed for the prioritization of functional candidates, and the regulatory impact of an ANXA1 -linked variant, rs75071948, was observed uniquely in luminal cells, and validated in vitro using CRISPR-mediated HDR. Fascinatingly, previous work has noted contradictory effects of ANXA1 upregulation, with worsened outcomes for some breast cancers, such as triple negative, basal like, and invasive ductal carcinoma, but improved outcomes in ductal carcinoma in situ. Given the emergence of diseases in breast tissue, such as breast cancer, in distinct cell types, this study demonstrates the importance of assessing cell type when considering the impacts of genetic variants on regulation and disease. [ABSTRACT FROM AUTHOR]