Dynamics of Mammary Epithelial Cell Differentiation. "What's SLUG Got to Do With It?".
Perturbations in stem cell activity and differentiation can lead to developmental
defects and cancer. How mutations in genes affect these processes are difficult to study
in mammals, and often require the creation of transgenic mice. Here, I use a novel
approach involving a quantitative model of cell-state transitions in vitro to gain
insights into how SLUG/SNAI2, a key developmenta... read morel transcription factor, modulates
mammary epithelial stem cell activity and differentiation in vivo. In the absence of
SLUG, stem cells fail to transition into basal progenitor cells, while existing basal
progenitor cells undergo luminal differentiation. Disruption of basal cell-state
transitions is offset by the proliferation and expansion of luminal progenitor cells;
together these changes result in abnormal mammary architecture and defects in tissue
function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity
necessary for tissue regeneration following transplantation and for cancer initiation
are lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by
recruiting the chromatin modifier, LSD1 (Lysine specific demethylase 1), to promoters of
lineage-specific genes to repress transcription. Together, these results reveal the
complex connection between stem cell dynamics and cellular differentiation, and
demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation
while unlocking stem cell transitions necessary for
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Genetics.
Advisor: Charlotte Kuperwasser.
Committee: Grace Gill, Philip Hinds, and James Schwob.
Keywords: Molecular biology, and Cellular biology.read less