P^21:5ZR<H $"( Chd1 and Paf1C control chromatin changes during cell differentiation and quiescence W;_Karl Ekwall .I Professor, Department of Biosciences and Nutrition, Karolinska Institutet, Sweden >@_]]A]]>[X\` 4=_108:O56B9&'# /6KNMKNC]]Y WQ7 DU My research group is studying epigenetic mechanisms with a current focus on chromatin remodelling enzymes. We use fission yeast and human cell lines as model systems. I will present results from two on-going projects in the laboratory. (1) Chd1 and Chd2 are two related a SWI2/SNF2 helicase enzymes with key roles in regulation of cell differentiation and these factors are overexpressed in leukemic cells. We have found through studies in fission yeast that Chd1 paralogs (Hrp1 and Hrp3) are important for nucleosome eviction at gene promoters and for regular spacing of nucleosomes in coding regions preventing cryptic antisense transcription. Our studies in human blood cells show that Chd1 and Chd2 are recruited by RNA pol II to gene promoters and enhancer regions and play a role in maintaining these regions nucleosome free. It is likely that Chd1 and Chd2 overexpression maintains altered gene expression patterns driving tumour formation. Therefore these enzymes could be suitable targets for epigenetic therapy. (2) Paf1 (RNA polymerase-associated factor 1) is another factor that interacts with RNA pol II and was identified by its ability to facilitate transcription elongation through chromatin. Paf1C is a multi-subunit complex that is conserved in eukaryotes. We recently found that Paf1 and Leo1, two core subunits of Paf1C, are involved control of heterochromatin assembly in fission yeast. In leo1! cells heterochromatin regions expand leading to silencing of genes. Using a new method to detect old and new histones in chromatin (H3-RITE) it was demonstrated that histone H3 turnover is reduced in leo1! cells and we propose a model where the stability of heterochromatin i.e. H3K9 methylation is counteracted by Paf1C. Interestingly, we recently discovered a role for Paf1C in quiescent fission yeast cells starved for nitrogen. leo1! cells are short-lived suggesting that uncontrolled heterochromatin assembly limits lifespan during long-term quiescence. +V-_,9 E)[3LIG6KN= 0564-59-5238\ J* T?[!%SFM6KNM \
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