Cell proliferation must be precisely controlled during development to produce tissues of the correct shape, composition and size. Terminal differentiation is often associated with exit from the cell cycle and coupled with a switch to a permanently postmitotic state. This is an important developmental process, as permanent exit from the cell cycle is likely to represent the most common cellular state in adult animals. Our data indicates a critical role for specific nucleosome remodelers in proper initiation and maintenance of cell cycle exit. This is consistent with our finding that accessibility at many gene regulatory elements also changes during cell cycle exit. The goal of our proposed research is to understand how cell cycle gene expression is shut down at the right places and times during development to establish and maintain a stable postmitotic state in differentiating tissues. To accomplish this, we propose three aims: 1. To define the specific gene expression and regulatory element accessibility changes that are due to cell cycle exit and how they are altered upon forced cell cycle re-entry 2. To determine how developmental signals coordinate cell cycle exit with differentiation events and 3. To understand the role of specific nucleosome remodelers in promoting cell cycle exit.
States of cellular withdrawal from the cell cycle or G0 can range from readily reversible to permanently postmitotic. This proposal addresses how different states of G0 are controlled during development and why some are more reversible than others. This work has the potential to impact a wide range of biological questions, as the proper control of G0 is critical for proper development and during tissue regeneration, but becomes disrupted in cancer.
