Mechanisms of epigenetic conversions in S.cerevisiae

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Eukaryotic genomes are packaged in a high-order complex called chromatin. Besides its obvious structural role, chromatin also plays a critical role in the regulation of gene expression. Depending on its level of condensation, chromatin can allow or prevent the access of transcription factors to their target genes. Importantly, such restrictive or permissive chromatin structures are heritable through multiple cell generations. Hence, heritable chromatin structures ensure the continuity of gene expression programs in the progeny. These chromatin transactions are the focus of the specialised field of epigenetics. Heritability of chromatin is not permanent. During the development of multicellular organisms numerous switches between the permissive and restrictive states of chromatin (called euchromatin and heterochromatin, respectively) take place. These switches contribute to cell differentiation and specialization and configure the so called epigenetic landscape of the specific tissue. In single cell eukaryotes such switches help to adapt to the environment. Devastating blood parasites such as Trypanosomes and Plasmodium use epigenetic switches to evade the immune system. In many health disorders, and notably in cancer, untimely epigenetic switches contribute to the development of the disease. Despite their apparent significance, epigenetic conversions and the molecular mechanisms that govern them are poorly understood. My research program is aiming to gain significant advances in this uncharted field of epigenetics. At certain genome positions the genes occasionally switch between the active or repressed states. This fascinating gene behaviour (known as Position-Effect-Variegation) has provided an excellent model system to study the conversions of chromatin. One such phenomenon, the so called Telomere-Position-Effect (TPE) in the baker yeast S.cerevisiae, has been pivotal in our understanding of how genes are regulated by chromatin structure. TPE has also been instrumental in the identification and characterisation of numerous chromatin modifying factors. In this application I describe a program, which is using TPE in S.cerevisiae to study the general mechanisms of epigenetic conversions in eukaryotes. I have already identified three genes that are involved in this process and have made some progress towards the understanding of the role of one of them, CAC1. It encodes subunits of a key Chromatin Assembly Factor, CAF-I. My short-term goals are to continue the studies on CAC1 by a combination of biochemical and genetic experiments. Another key direction in my proposal is to find a common mechanism shared by CAC1 and another gene that was identified as a regulator of epigenetic switches (RRM3). The outcome of this research program will contribute to fundamental academic knowledge, but will also strongly appeal to researchers in the field of health sciences and cancer.