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Genome-wide patterns of histone modifications in fission yeast
Södertörn University, School of Life Sciences. Karolinska Institutet.
Södertörn University, School of Life Sciences. Karolinska Institutet.
Södertörn University, School of Life Sciences. Karolinska Institutet.
2006 (English)In: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 14, no 1, 95-105 p.Article in journal (Refereed) Published
Abstract [en]

We have used oligonucleotide tiling arrays to construct genome-wide high-resolution histone acetylation maps for fission yeast. The maps are corrected for nucleosome density and reveal surprisingly uniform patterns of modifications for five different histone acetylation sites. We found that histone acetylation and methylation patterns are generally polar, i.e. they change as a function of distance from the ATG codon. A typical fission yeast gene shows a distinct peak of histone acetylation around the ATG and gradually decreased acetylation levels in the coding region. The patterns are independent of gene length but dependent on the gene expression levels. H3K9Ac shows a stronger peak near the ATG and is more reduced in the coding regions of genes with high expression compared with genes with low expression levels. H4K16Ac is strongly reduced in coding regions of highly expressed genes. A second microarray platform was used to confirm the 5' to 3' polarity effects observed with tiling microarrays. By comparing coding region histone acetylation data in HDAC mutants and wild type, we found that hos2 affects primarily the 5' regions, sir2 and clr6 affect middle regions, and clr6 affects 3' regions. Thus, mechanisms involving different HDACs modulate histone acetylation levels to maintain a 5' to 3' polarity within the coding regions.

Place, publisher, year, edition, pages
2006. Vol. 14, no 1, 95-105 p.
National Category
Biochemistry and Molecular Biology Genetics
Identifiers
URN: urn:nbn:se:sh:diva-14309DOI: 10.1007/s10577-005-1023-4ISI: 000235703700009PubMedID: 16506099ScopusID: 2-s2.0-33644614845OAI: oai:DiVA.org:sh-14309DiVA: diva2:468117
Available from: 2011-12-20 Created: 2011-12-20 Last updated: 2016-08-05Bibliographically approved
In thesis
1. Genome-wide study of HDACs and transcription in Schizosaccharomyces pombe
Open this publication in new window or tab >>Genome-wide study of HDACs and transcription in Schizosaccharomyces pombe
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The eukaryotic genome has to be organized to fit into the cell and this is achieved by packing of DNA into chromatin. The basic repeating structural unit of chromatin is the nucleosome, which consists of DNA wrapped around histone proteins. Histones are subjected to multiple covalent posttranslational modifications including, acetylation, methylation, phosphorylation, and ubiquitination. These modifications take part in gene regulation by changing the structure of chromatin and by recruiting gene regulatory proteins. Histone acetylation can be removed by histone deacetylases (HDACs), which are highly conserved enzymes that regulate a diverse number of biological processes including gene expression and chromosome segregation, and have shown to be closely linked to major diseases like cancer. This thesis described the genome-wide role of HDACs and transcription in S. pombe. We studied the genome wide binding targets and enzymatic specificity of different S. pombe HDACs and uncovered different roles for the enzymes at silent regions and in repression and activation of gene expression. We proposed that independent of gene length, a typical fission yeast gene shows a 5 to 3 polarity, i.e., the histone acetylation levels peak near the ATG and gradually decrease in the coding regions. We also observed that different HDACs are responsible for different position within the ORF regions. Our genome-wide study of two different Mediator complexes reviled that they displayed similar binding patterns, and interactions with promoters and upstream activating sequences correlated with increased transcription activity. We also found that Mediator associates with the downstream coding region of many genes. We finally developed a method, E-map, which made it possible to systematically construct haploid double mutants. This method was used for constructing genome-wide genetic interaction maps of HDACs in S. pombe. From our preliminary results we discovered a new link between the Class III HDACs and a biosynthesis protein. Our data also suggest that different HDACs are involved in distinct biological processes.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet, 2010. 51 p.
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-30694 (URN)978-91-7409-970-6 (ISBN)
Supervisors
Available from: 2016-08-04 Created: 2016-08-04 Last updated: 2016-08-04Bibliographically approved
2. Genome-wide patterns of histone modifications in fission yeast
Open this publication in new window or tab >>Genome-wide patterns of histone modifications in fission yeast
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DNA is wrapped almost two times around a group of proteins called histones to form a chromosomal structure known as the nucleosome. Both DNA and histones can be modified with different chemical tags by several enzymes to activate or suppress a particular gene or group of genes. Histones can be covalently modified at several places. Among many different types of post-translational histone modifications, histone acetylation and methylation are two important modification types that are associated with transcriptional activation and repression. Histone acetylation and methylation can be added by histone acetyltransferases (HATs) and histone methyletransferases (HMTs), whereas these modifications can be removed by histone deacetylases (HDACs) and histone demethylases (HDMs). Histone modifications are not only involved in the regulation of gene expression, but also in DNA-based processes, such as replication, repair, and the formation and maintenance of heterochromatin. Combinations of modified and unmodified states of histones can form distinct histone modification patterns. In many different genome-wide studies, it was observed that a distinctive pattern of histone modification in various organisms is important for gene regulation, DNA replication, chromosome segregation and heterochromatin-mediated silencing. In this thesis, we have conducted several genome-wide investigations to uncover different histone modification patterns and their roles in transcriptional control in fission yeast. Our analysis of six different HDACs in fission yeast showed that Clr6 and Clr3 are mainly involved in keeping repressed genes silent; Sir2 and Hst2 repress non-expressed genes, and Hst4 acts globally to reduce gene expression, whereas Hos2 is required for the activation of gene expression. By investigating the influence of each HDAC on nucleosome density, we found that all sirtuins and Hos2 enzymes are required to maintain normal nucleosome density and distribution in the S. pombe genome. We have reported that histone acetylation patterns show a 5` to 3` polarity, i.e., the modification levels peak near the ATG and gradually decrease in the coding regions. We also found that histone acetylation patterns depend on gene expression but are independent of gene length. Comparing our data with other published datasets, we observed that different HDAC mutants affect acetylation in different parts of open reading frames (ORFs). We have demonstrated that histone H4 acetylation proceeds in the direction from K16 to K5, consistent with a `zip` model that may be involved in transcriptional control. Our analysis revealed antagonistic crosstalk between H3K36me2/me3 and H3K27ac at promoter regions. We observed that histone H3 K18, K27 and K9 acetylation positively correlate with gene expression, and a conserved pattern was also reported in other organisms. Finally, we report that histone H4K20me1 is strongly linked to active genes, whereas H4K20me3 is associated with weakly expressed genes. Our analysis further shows that H4K20me1 modification levels peak at 3‟UTR regions in active genes. Thus, our analysis revealed many different aspects of histone modification patterns and their roles in transcriptional control in fission yeast.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet, 2010. 59 p.
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-30695 (URN)
Supervisors
Available from: 2016-08-05 Created: 2016-08-04 Last updated: 2016-08-05Bibliographically approved

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