Cell-type-specific epigenomic variations associated with BRCA1 mutation in pre-cancer human breast tissues

BRCA1 germline mutation carriers are predisposed to breast cancers. Epigenomic regulations have been known to strongly interact with genetic variations and potentially mediate biochemical cascades involved in tumorigenesis. Due to the cell-type specificity of epigenomic features, profiling of individual cell types is critical for understanding the molecular events in various cellular compartments within complex breast tissue. Here we report cell-type specific profiling of genome-wide histone modifications, including H3K27ac and H3K4me3 in basal, luminal progenitor, mature luminal, and stromal cells, extracted from pre-cancer BRCA1 mutation carriers and non-carriers, using a low-input technology. We discover that basal and stromal cells present the most substantial epigenomic differences between mutation carriers and non-carriers while luminal progenitor and mature luminal cells are relatively unchanged with the mutation. Furthermore, the epigenomic changes in basal cells due to BRCA1 mutation appear to facilitate their transformation into luminal progenitor cells. Our findings shed light on the pre-cancer epigenomic dynamics due to BRCA1 mutation and how they may contribute to eventual development of basal-like breast cancer. H3K27ac and H3K4me3 were profiled in four cell types from healthy breast tissues in women with and without the BRCA1 gene mutation. The cell types include basal cells (BCs), luminal progenitor cells (LPs), mature luminal cells (MLs), and stromal cells (SCs). We examined five non-carriers (BRCA1+/+: NC-1, NC-2, NC-3, NC-4, and NC-5) and three BRCA1 mutation carriers (BRCA1mut/+: MUT-1, MUT-2, and MUT-3). The profiling was conducted using MOWChIP-seq technology (Cao et al. Nature Methods, 12 (2015) 959-962; Zhu et al. Nature Protocols 14 (2019) 3366-3394). **The submitter declares that the raw data will be made available in dbGaP due to patient privacy concerns.**