Ageing, either natural or disease-driven, is accompanied by global epigenetic changes including the disruption of silent heterochromatin. Recently, a physical and functional connection has been made between the chromatin changes that occur as cells age and the NuRD chromatin remodeling complex. NuRD is a unique chromatin modifying complex in that it harbors the physical association of histone deacetylase as well as nucleosome remodelling activity. While seemingly absent from budding yeast, a highly similar complex, SHREC, has been purified from the fission yeast S. pombe which appears to regulate heterochromatin in a manner similar to mammalian NuRD. This proposal seeks to investigate the molecular and biochemical basis for SHREC- dependent spreading of heterochromatin using the tractability of yeast genetics and in vitro biochemistry with the intent of characterizing the importance of conserved chromatin binding modules as well as activity of the complex in modifying nucleosomal substrates.
As cells age, they accumulate chromatin defects that lead to DNA damage and alteration of gene expression. Determining the precise mechanisms regulating these epigenetic changes should prove useful in the understanding and possible therapeutic intervention of normal and hyper-accelerated ageing.
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