Molecular mechanisms reprogramming transcription in quiescent cells

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The long-term goal of the proposed research is to characterize the molecular mechanism(s) by which cells are reprogrammed into quiescence. This reprogramming is essential for cells to maintain viability over long periods of time without divisions, such as quiescent stem cells and memory lymphocytes. On the other hand, this reprogramming also allows early-disseminated cancer cells to evade treatment by maintaining their state of quiescence. Therefore, deciphering the mechanisms and factors involved in cellular quiescence is both a fundamental biological question and informative in health and disease. We are approaching this in a systematic manner by focusing on a model organism, the fission yeast S. pombe. This model has a ‘minimal set’ of genes allowing viable long-term quiescence, and retained epigenetic mechanisms such as histone marks and RNA interference, which are essential in non-dividing cells. By identifying this minimal set and using high-throughput approaches available in fission yeast, our goal is to understand the basic principles and key components of reprogramming in quiescence, without the confounding effects due to the added complexity of multicellular organisms, where differentiation and intercellular communication occur and affect quiescence. Among several pathways that we have found to be essential for quiescence maintenance, we are focusing specifically on two complementary factors, which are not only conserved across eukaryotes, but also most likely to impact our understanding of reprogramming: in aim 1, we will study how a core component of the Mediator complex is essential specifically in quiescent cells to maintain basal transcriptional activity; in aim 2, we will focus on ERH, a small enigmatic protein, which acts as a repressor of transcription in quiescence. We will employ a combination of genetic, genomic, biochemistry and bioinformatics approaches to understand how these two complementary regulators shape gene expression in quiescent cells. Because both Mediator and ERH are mis-expressed in cancers with strong metastatic potential, we expect our results to shed some light not only on transcriptional reprogramming in physiological quiescent cells, but also on how this process is mis-regulated in tumor dormancy.