| Summary: | Chromatin is a nucleoprotein complex packaging DNA inside the cell nucleus and is of crucial relevance for genome regulation. Its structure is highly dynamic undergoing post-translational modifications, replacement by histone variants, and ATP-dependent remodelling. My dissertation aims to better understand the regulation of chromatin by studying the structure and function of a chromatin modifier, mapping chromatin modifications at a genome-wide scale, and linking modification patterns to cellular functions in the model organism Saccharomyces cerevisiae. Multiple chromatin modifying and transcription complexes contain a YEATS domain, and their misregulation has been implicated in the development of cancer. This study recognizes the evolutionary conservation of the YEATS domain from yeast to human, presents its structural composition as well as its function in depositing the histone variant H2A.Z. Besides histone variants, histone modifications determine chromatin structure and often co-occur in certain genomic regions. Histone H3 lysine 79 methylation is one such modification that adds an additional level of complexity being either mono-, di- or trimethylated (H3K79me1, me2, me3). In this work, I show that these methylation states are functionally not redundant as previously proposed, and that H3K79 di- and trimethylation are associated with different regions of the genome. In contrast to H3K79me3, H3K79me2 marks M/G1 cell cycle regulated genes and its levels change during the cell cycle. The trigger for trimethylation of H3K79, as well as for trimethylation of lysine 4 on histone H3 (H3K4me3), is monoubiquitination of histone H2B (H2BK123ub). The map of H2BK123ub that I present herein demonstrates its role as upstream regulator for H3K79me3 and H3K4me3 on a genome-wide scale. Removal of the transient H2BK123ub mark is facilitated by the deubiquitinases Ubp8 and Ubp10. I herein reveal that they mainly act at distinct genomic loci. While Ubp8 removes H2BK123ub at sites enriched for H3K4me3, Ubp10 functions at those marked by H3K79me3. Finally, my thesis describes chromatin signatures of multiple modifications, and finds the combination of H2BK123ub, H3K4me3, and H3K36me3 to be specific for highly transcribed genes, including those containing introns. In this context, I show evidence that link the histone H2B ubiquitin ligase Bre1 to mRNA splicing. === Medicine, Faculty of === Medical Genetics, Department of === Graduate
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