Epigenomics of mammary gland development

Abstract

Differentiation of stem cells into highly specialised cells requires gene expression changes brought about by remodelling of the chromatin architecture. During this lineage-commitment process, the majority of DNA needs to be packaged into inactive heterochromatin, allowing only a subset of regulatory elements to remain open and functionally required genes to be expressed. Epigenetic mechanisms such as DNA methylation, post-translational modifications to histone tails, and nucleosome positioning all potentially contribute to the changes in higher order chromatin structure during differentiation. The mammary gland is a particularly useful model to study these complex epigenetic processes since the majority of its development is postnatal, the gland is easily accessible, and development occurs in a highly reproducible manner. Inappropriate epigenetic remodelling can also drive tumourigenesis; thus, insights into epigenetic remodelling during mammary gland development advance our understanding of breast cancer aetiology. We review the current literature surrounding DNA methylation and histone modifications in the developing mammary gland and its implications for breast cancer.

Cell-type-specific epigenomic variations associated withBRCA1mutation in pre-cancer human breast tissues

“…Furthermore, our analysis of the cell-type-specific genes and TFs also reveal that MUT BCs resemble LPs. Such resemblance was in accordance with previous reports on the presence of LP-fated cells and bi-potent mammary stem cells in the basal compartment (Pal et al 2017;Holliday et al 2018). Thus we propose that the precancerous process within BRCA1 mutation carriers may start with substantial epigenomic changes in basal cells among all epithelial cell types and these basal cells share similarity with luminal progenitor cells.…”

“…However, epithelial cell fate commitment is also present only in BCs. Cells within the BC compartment have been previously shown to have the potential to differentiate into LPs (Holliday et al 2018).…”

“…This is unexpected as LPs have been implicated as the driver in the onset of BRCA1-mutation associated breast cancer (Lim et al 2009b). Thus we examine the possibility of basal cells differentiating into luminal cells, as proposed in previous literature (Holliday et al 2018). Table S9).…”

Epigenetics in Inflammatory Breast Cancer: Biological Features and Therapeutic Perspectives

“…The epigenetic alterations modulate the chromatin accessibility and regulate the gene expression during the differentiation of stem into differentiated cells [49], being essential for the transcriptional plasticity and tissue-specific cell differentiation throughout the mammary gland development [50,51]. The mammary gland shows several changes in its architecture throughout the lifetime, mainly in response to hormones.…”

“…A secondary and tertiary side branching and the formation of alveolar units that produce and secrete milk occur during pregnancy and lactation. Finally, the mammary gland is reshaped to the quiescent state by the involution process (post-lactation weaning period) [51,52]. The deregulation of the epigenetic events involved in the mammary gland development and remodeling could result in the clonal proliferation of progenitor cancer cells in breast tissue driving breast carcinogenesis [53,54].…”