2015.7.16 Machines Controlling Quiescence Heterogeneity by an Rb-E2F Bistable Switch
题目：Machines Controlling Quiescence Heterogeneity by an Rb-E2F Bistable Switch
报告人： Dr. Guang Yao
Assistant Professor，Department of Molecular and Cellular Biology,
University of Arizona, Tucson, USA
Quiescence is a “sleep-like” non-proliferative cellular state that plays a critical role in the health of higher organisms. Reactivating quiescent cells (e.g., fibroblasts, lymphocytes, and stem cells) to proliferate is fundamental to tissue repair and regeneration. Many diseases, such as fibrosis, autoimmune disease, cancer, and aging, exhibit a dysregulation of cellular quiescent state. Often described as the “G0 phase”, quiescence is in fact not a homogeneous state. As cells remain quiescent for longer durations, they move progressively “deeper” into quiescence, exiting from which requires prolonged and stronger growth stimulation. Importantly, cells in deep quiescence do not undergo senescence or cell death, as they can still proliferate upon addition of sufficient serum. Nevertheless, underlying mechanisms of deep vs. shallow quiescence remain an enigma, and represent a currently underappreciated layer of complexity in growth control. Previously, we showed that the retinoblastoma (Rb)-E2F pathway functions as a bistable gene switch, converting graded and transient growth signals into an all-or-none E2F activity, which underlies the all-or-none transition from quiescence to proliferation. Here by coupling computer modeling and single-cell measurements, we show that quiescence depth is controlled by the activation threshold of the Rb-E2F bistable switch. We further show that different Rb-E2F pathway components have different efficacies in modulating quiescence depth. We also show that by affecting the Rb-E2F activation threshold, regulators of Notch pathway and circadian clock, as well as the metabolic state at quiescence entry modulate the depth of quiescence, and correspondingly, the heterogeneity of quiescence exit in response to growth signals. Further elucidating the control mechanisms underlying quiescence depth may help develop novel strategies to correct abnormal quiescent states of diseased cells.