Lineage commitment and cell differentiation are processes driven by the re-organization of chromatin accessibility, which allows fate-specific transcription factors (TFs) to control gene regulatory networks. This mechanism is modulated by factors that change the “active” or “repressive” state of genes via deposition (writers) or removal (erasers) of post-translational modifications at histone tails. An additional layer of regulation comes from factors that associate with specific histone modifications (readers) to modulate transcriptional output. This represents a fundamental process by which pluripotent stem cells mature into distinct germ layers during embryogenesis, and for the specialization of adult stem cells into tissue-specific, differentiated cell types.
In the case of mammary epithelial cells, maintenance and remodeling of chromatin regulates the progression of MaSC into luminal and myoepithelial cell fates. This modification of the epigenetic landscape may also represent a signature that allows differentiated mammary epithelial cells to respond to hormonal variation during pubescence, pregnancy, lactation and involution. Over the past few years, we combined transcriptome profile and flow cytometry analysis to optimize a method that allows the isolation of major mammary epithelial cell types, including mammary gland stem cells. Using this strategy we were able to map with great resolution the transcriptional state and the epigenomic regulation of such cell types at distinct stages of mammary gland development.
Ongoing efforts seek now to extend our research in two main arms: a) the molecular characterization of pregnancy-induced breast cancer protection, a long term effect that pregnancy exerts on decreasing the risk to develop breast cancer in rodents and humans; and b) the characterization of new epigenomic modulators of mammary stem cell self-renewal and lineage commitment, with the goal to find candidates that could also be used to target aggressive forms of breast cancer.
Our ultimate goal is to characterize the effects of the enhancer landscape on normal and malignant development of mammary epithelial cells.