sh.sePublications
Change search
ReferencesLink to record
Permanent link

Direct link
Genome-wide patterns of histone modifications in fission yeast
Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intstitutet.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)Text
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: urn:nbn:se:sh:diva-30695OAI: oai:DiVA.org:sh-30695DiVA: diva2:951011
Supervisors
Available from: 2016-08-05 Created: 2016-08-04 Last updated: 2016-08-05Bibliographically approved
List of papers
1. Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast
Open this publication in new window or tab >>Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast
Show others...
2005 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 24, no 16, 2906-2918 p.Article in journal (Refereed) Published
Abstract [en]

We have conducted a genomewide investigation into the enzymatic specificity, expression profiles, and binding locations of four histone deacetylases (HDACs), representing the three different phylogenetic classes in fission yeast ( Schizosaccharomyces pombe). By directly comparing nucleosome density, histone acetylation patterns and HDAC binding in both intergenic and coding regions with gene expression profiles, we found that Sir2 ( class III) and Hos2 ( class I) have a role in preventing histone loss; Clr6 ( class I) is the principal enzyme in promoter-localized repression. Hos2 has an unexpected role in promoting high expression of growth-related genes by deacetylating H4K16Ac in their open reading frames. Clr3 ( class II) acts cooperatively with Sir2 throughout the genome, including the silent regions: rDNA, centromeres, mat2/3 and telomeres. The most significant acetylation sites are H3K14Ac for Clr3 and H3K9Ac for Sir2 at their genomic targets. Clr3 also affects subtelomeric regions which contain clustered stress- and meiosis-induced genes. Thus, this combined genomic approach has uncovered different roles for fission yeast HDACs at the silent regions in repression and activation of gene expression.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-14447 (URN)10.1038/sj.emboj.7600758 (DOI)000231789300007 ()16079916 (PubMedID)2-s2.0-72949109535 (ScopusID)
Available from: 2012-01-19 Created: 2011-12-23 Last updated: 2016-12-01Bibliographically approved
2. Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing
Open this publication in new window or tab >>Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing
Show others...
2007 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 26, no 10, 2477-2488 p.Article in journal (Refereed) Published
Abstract [en]

Expression profiling, ChiP-CHIP and phenotypic analysis were used to investigate the functional relationships of class III NAD(+)-dependent HDACs (Sirtuins) in fission yeast. We detected significant histone acetylation increases in Sirtuin mutants at their specific genomic binding targets and were thus able to identify an in vivo substrate preference for each Sirtuin. At heterochromatic loci, we demonstrate that although Hst2 is mainly cytoplasmic, a nuclear pool of Hst2 colocalizes with the other Sirtuins at silent regions (cen, mat, tel, rDNA), and that like the other Sirtuins, Hst2 is required for rDNA and centromeric silencing. Interestingly we found specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation. Hst2 directly represses genes involved in transport and membrane function, whereas Hst4 represses amino-acid biosynthesis genes and Tf2 retrotransposons. A specific role for Hst4 in Tf2 50 mRNA processing was revealed. Thus, Sirtuins share functions at many genomic targets, but Hst2 and Hst4 have also evolved unique functions in gene regulation.

National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:sh:diva-14223 (URN)10.1038/sj.emboj.7601690 (DOI)000247083100004 ()17446861 (PubMedID)2-s2.0-34249001997 (ScopusID)
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2016-08-05Bibliographically approved
3. 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
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.

National Category
Biochemistry and Molecular Biology Genetics
Identifiers
urn:nbn:se:sh:diva-14309 (URN)10.1007/s10577-005-1023-4 (DOI)000235703700009 ()16506099 (PubMedID)2-s2.0-33644614845 (ScopusID)
Available from: 2011-12-20 Created: 2011-12-20 Last updated: 2016-08-05Bibliographically approved
4. Genome-wide mapping of histone modifications and mass spectrometry reveal H4 acetylation bias and H3K36 methylation at gene promoters in fission yeast
Open this publication in new window or tab >>Genome-wide mapping of histone modifications and mass spectrometry reveal H4 acetylation bias and H3K36 methylation at gene promoters in fission yeast
Show others...
2010 (English)In: Epigenomics, ISSN 1750-1911, Vol. 2, no 3, 377-393 p.Article in journal (Refereed) Published
Abstract [en]

To map histone modifications with unprecedented resolution both globally and locus-specifically, and to link modification patterns to gene expression. Materials & methods: Using correlations between quantitative mass spectrometry and chromatin immunoprecipitation/microarray analyses, we have mapped histone post-translational modifications in fission yeast (Schizosaccharomyces pombe). Results: Acetylations at lysine 9, 18 and 27 of histone H3 give the best positive correlations with gene expression in this organism. Using clustering analysis and gene ontology search tools, we identified promoter histone modification patterns that characterize several classes of gene function. For example, gene promoters of genes involved in cytokinesis have high H3K36me2 and low H3K4me2, whereas the converse pattern is found ar promoters of gene involved in positive regulation of the cell cycle. We detected acetylation of H4 preferentially at lysine 16 followed by lysine 12, 8 and 5. Our analysis shows that this H4 acetylation bias in the coding regions is dependent upon gene length and linked to gene expression. Our analysis also reveals a role for H3K36 methylation at gene promoters where it functions in a crosstalk between the histone methyltransferase Set2(KMT3) and the histone deacetylase Clr6, which removes H3K27ac leading to repression of transcription. Conclusion: Histone modification patterns could be linked to gene expression in fission yeast.

National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-13987 (URN)10.2217/EPI.10.18 (DOI)000278533000009 ()2-s2.0-77954091620 (ScopusID)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2011-12-16 Created: 2011-12-15 Last updated: 2016-08-05Bibliographically approved
5. Gnome wide mapping suggests different roles for H4K20me1 and H4K20me3 in gene expression
Open this publication in new window or tab >>Gnome wide mapping suggests different roles for H4K20me1 and H4K20me3 in gene expression
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-30697 (URN)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2016-08-05 Created: 2016-08-05 Last updated: 2016-08-05Bibliographically approved

Open Access in DiVA

No full text

Other links

Fulltext

Search in DiVA

By author/editor
Sinha, Indranil
By organisation
Molecular biology
Biological Sciences

Search outside of DiVA

GoogleGoogle Scholar

Total: 8 hits
ReferencesLink to record
Permanent link

Direct link