Living cells can be categorized in two classes according to their proliferation status: either they are dividing, or they can enter a quiescent resting phase termed G0. While many studies have previously focused on the cell cycle regulation of proliferating cells, the mechanisms underlying entry into the quiescent resting phase G0, as well as the biological characteristics of the G0 phase itself, are not well defined yet. Recent studies have shown that signaling cascades control entry into the G0 phase by regulating the expression of specific cohorts of genes. In S. cerevisiae, G0 gene expression is mainly positively controlled by the Rim15 kinase, and by the Gis1 transcription factor. The molecular mechanisms by which Rim15 regulates those genes remain largely unknown. Genes are embedded in a chromatin context (DNA is wrapped around nucleosomes and associates with other proteins to form chromatin), and regulation of their expression requires the concerted action of transcription factors and histone-modifying enzymes. Here, we propose to identify chromatin modifying enzymes that mediate G0-specific chromatin modifications, and to study how these activities are coordinated with the functions of Rim15 and Gis1. We expect that these studies will contribute to our general understanding of chromatin modifications and their role in the establishment of the quiescence program, and to a clearer view of the characteristics of the G0 phase itself.
Context and significance
Deregulation of chromatin modifying enzymes can be associated with initiation, progression, and maintenance of carcinogenesis in humans. In this context, agents acting on chromatin modifying enzymes, as for example histone deacetylase inhibitors, are now considered as therapeutic drugs in the fight against certain forms of cancer. Identification and molecular characterization of the mode of action of conserved chromatin modifying enzymes, as proposed here, may therefore not only elucidate the mechanisms by which cells enter into and remain in a quiescent G0 state, but also contribute to our understanding of cellular transformation in multicellular organisms.
Our aim is to address how Rim15 and Gis1 regulate G0 genes in concert with chromatin modifying enzymes. In a first set of experiments, we will study whether Rim15 communicates to the promoters of specific target genes through the transcription factor Gis1, and/or through its own recruitment. Second, we will determine which chromatin modifying factors may be involved in Rim15/Gis1-dependent gene regulation, how they regulate their target genes, and to what extend they participate in the regulation of the quiescent state.