Mechanisms and functions of chromatin regulation for cell-cycle control

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Project Summary/Abstract which cell-cycle is regulated, with an emphasis on mechanisms of cell quiescence through chromatin regulation. Eukaryotic cells, from single cell organisms to humans, spend most of their time in quiescence, in which cell exit mitotic cell-cycle in a reversible fashion for long-term survival. Proper control of entry into, maintenance of, and exit from quiescence is essential for cell survival, normal development of organisms, stem cell maintenance and prevention of cancer. However, molecular mechanisms underlying quiescence remains largely unknown. Chromatin regulation plays integral roles in a wide variety of DNA-dependent processes, including transcription, DNA replication, DNA repair, recombination, kinetochore formation, and DNA damage checkpoint response. Therefore, elucidating the mechanisms of chromatin regulation is a necessary prerequisite for understanding how these essential processes are controlled. One of the major challenges in studying chromatin regulation is to elucidate how chromatin regulation affects such a wide variety of processes in the context of important biological contexts, such as cell cycle control and cell differentiation. This is a particularly important challenge, because it was recently determined that mutations in chromatin regulators represent one major class of so called cancer driver mutations, and how these mutations accerelate cancer development remains unknown. Therefore, elucidating the mechanisms of chromatin regulation impacts not only the researchers who study fundamental principle of DNA-dependent processes, but also those who investigate cancer biology and mechanisms of genome stability maintenance. It was recently found that the budding yeast S. cerevisiae can enter quiescent state that share many properties with mammalian quiescence, and a method to purify the quiescent cell was developed. Taking advantage of this system, we have found strong evidence that degradation of specific sets of mRNA is essential for quiescence entry. This strongly suggest the presence of currently unknown mechanism to regulate quiescence entry. We have also found that the high-order structure of chromatin is regulated in quiescence in a way distinct from exponentially growing cells. First, we found that condensin, a highly conserved regulator of chromatin higher-order structure, globally re-localizes during quiescence entry and play key roles in chromatin domain structure in quiescent cells. Secondly, we found that nucleosome arrays are folded into different fashion in quiescent cells. We will take advantage of these recent findings and determine the molecular basis for these observations, which will address a significant gap in our current knowledge about mechanisms underlying quiescence and higher-order chromatin structure.