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Regulation of alternative splicing
Dušková, Eva ; Staněk, David (advisor) ; Trejbalová, Kateřina (referee)
Alternative splicing is an important cellular mechanism. It allows to produce multiple protein isoforms from a limited number of genes. Regulation of alternative splicing involves cis-acting elements on pre-mRNA and trans-acting splicing factors (SR and hnRNP proteins). Because splicing occurs co-transcriptionaly, chromatin structure appears to have a role in the regulation of alternative splicing. We have studied the effect of histone acetylation on alternative splicing. We have prepared splicing reporter for alternative EDB exon, which is part of the fibronectin gene. We have shown, that the inhibition of histone deacetylases affects splicing pattern of EDB exon from the reporter in the same way as the splicing of the endogenous EDB exon. Furthermore, we have shown, that the structure of the promoter affects splicing of alternative EDB exon from splicing reporter. Currently we have found out, that the structure of the promoter influences the degree of histone H4 acetylation. Inclusion of alternative EDB exon in mRNA was inversely proportional to histon acetylation on the reporter. This work might explain why various promoters have different splicing patterns of alternative exons.
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The relationship between chromatin organization and RNA splicing
Icha, Jaroslav ; Valentová, Anna (referee) ; Staněk, David (advisor)
It is well known that RNA splicing and other pre-mRNA processing reactions happen cotranscriptionally. Surprisingly, there were recently discovered some chromatin features that had uneven distribution between exons and introns, which directly links chromatin organisation to splicing. This work summarizes all the studies that detected these chromatin patterns on exons and discuss their inconsistencies. In these studies nucleosomes were found to be preferentially positioned on exons, specific histone modifications and DNA methylation were also enriched on exons. These local patterns of chromatin organisation were evolutionarily conserved from mammals (human and mouse) to worm C. elegans and fly D. melanogaster. Their findings indicate that the role for chromatin structure in pre-mRNA splicing is to promote exon recognition. There are two mechanisms proposed for this role of chromatin in splicing. The first one is influence on RNA polymerase II elongation speed, and the second is specific recruitment of splicing machinery. In the near future we can expect studies searching for concrete examples of these two mechanisms and assessing their significance. Indeed it was reported very recently that H3K36me3 regulates alternative splicing via the second mechanism.
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