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Characterization of Gcn5 histone acetyltransferase in Schizosaccharomyces pombe
Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The organisation of eukaryotic DNA into chromatin provides a natural barrier that prevents full access to the DNA thereby inhibiting events such as transcription, replication and repair. In order for these DNA-related events to occur, the chromatin needs to be modified by chromatin remodelling or, by reversible post-translational modifications. Histone acetylation is such a modification and is essential of numerous DNA related events. The enzymes involved in this event are conserved throughout evolution, underscoring their importance. This thesis describes the role of the conserved histone acetyltransferase (HAT) Gcn5 in transcriptional regulation in Schizosaccharomyces pombe. Here we show that Gcn5 plays an important role in stress response. We map genome-wide Gcn5 occupancy and show that Gcn5 is predominantly localized to coding regions of highly transcribed genes. We also map H3K14 acetylation during salt stress and show that Gcn5 collaborates antagonistically with the class-II histone deacetylase, Clr3, to modulate H3K14ac levels and transcriptional elongation. The interplay between Gcn5 and Clr3 is crucial for the regulation of many stress-response genes. Our findings suggest a new role for Gcn5 during transcriptional elongation, in addition to its known role in transcriptional initiation. We also investigate the interactions between Gcn5 and other histone deacetylases and acetyltransferases and show overlapping functionality between Gcn5 and another histone acetyltransferase, Mst2, in stress response, regulation of subtelomeric genes and DNA damage repair. Finally, we show that the role of Gcn5 in stress response is mediated by its catalytic activity and that its function in stress response is conserved among yeast species.

Place, publisher, year, edition, pages
Stockholm: Karolinska instiutet , 2009. , 31 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:sh:diva-30871ISBN: 9789174095494 (print)OAI: oai:DiVA.org:sh-30871DiVA: diva2:971201
Public defence
2009-08-28, 10:00
Opponent
Supervisors
Available from: 2016-09-15 Created: 2016-09-15 Last updated: 2016-09-15Bibliographically approved
List of papers
1. Stress-specific role of fission yeast Gcn5 histone acetyltransferase in programming a subset of stress response genes
Open this publication in new window or tab >>Stress-specific role of fission yeast Gcn5 histone acetyltransferase in programming a subset of stress response genes
2006 (English)In: Eukaryotic Cell, ISSN 1535-9778, E-ISSN 1535-9786, Vol. 5, no 8, 1337-1346 p.Article in journal (Refereed) Published
Abstract [en]

Gcn5 is a coactivator protein that contributes to gene activation by acetylating specific lysine residues within the N termini of histone proteins. Gcn5 has been intensively studied in the budding yeast, Saccharomyces cerevisiae, but the features of genes that determine whether they require Gcn5 during activation have not been conclusively clarified. To allow comparison with S. cerevisiae, we have studied the genome-wide role of Gcn5 in the distantly related fission yeast, Schizosaccharomyces pombe. We show that Gcn5 is specifically required for adaptation to KCl- and CaCl2-mediated stress in S. pombe. We have characterized the genome-wide gene expression responses to KCl stress and show that Gcn5 is involved in the regulation of a subset of stress response genes. Gcn5 is most clearly associated with KCl-induced genes, but there is no correlation between Gcn5 dependence and the extent of their induction. Instead, Gen5-dependent KCl-induced genes are specifically enriched in four different DNA motifs. The Gcn5-dependent KCl-induced genes are also associated with biological process gene ontology terms such as carbohydrate metabolism, glycolysis, and nicotinamide metabolism that together constitute a subset of the ontology parameters associated with KCl-induced genes.

National Category
Microbiology
Identifiers
urn:nbn:se:sh:diva-14285 (URN)10.1128/EC.00101-06 (DOI)000239778700015 ()16896217 (PubMedID)2-s2.0-33747361359 (Scopus ID)
Available from: 2011-12-20 Created: 2011-12-20 Last updated: 2017-07-19Bibliographically approved
2. HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress
Open this publication in new window or tab >>HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress
Show others...
2009 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 10, no 9, 1009-1014 p.Article in journal (Refereed) Published
Abstract [en]

Histone acetylation and deacetylation are important for gene regulation. The histone acetyltransferase, Gcn5, is an activator of transcriptional initiation that is recruited to gene promoters. Here, we map genome-wide Gcn5 occupancy and histone H3K14ac at high resolution. Gcn5 is predominantly localized to coding regions of highly transcribed genes, where it collaborates antagonistically with the class-II histone deacetylase, Clr3, to modulate H3K14ac levels and transcriptional elongation. An interplay between Gcn5 and Clr3 is crucial for the regulation of many stress-response genes. Our findings suggest a new role for Gcn5 during transcriptional elongation, in addition to its known role in transcriptional initiation.

National Category
Cell Biology
Identifiers
urn:nbn:se:sh:diva-13886 (URN)10.1038/embor.2009.127 (DOI)000269449500020 ()19633696 (PubMedID)2-s2.0-69949172827 (Scopus ID)
Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2017-07-18Bibliographically approved
3. Expression profiling of S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation
Open this publication in new window or tab >>Expression profiling of S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation
Show others...
2010 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, 59Article in journal (Refereed) Published
Abstract [en]

Background: Histone acetyltransferase enzymes (HATs) are implicated in egulation of transcription. HATs from different families may overlap in arget and substrate specificity. esults: We isolated the elp3(+) gene encoding the histone cetyltransferase subunit of the Elongator complex in fission yeast and haracterized the phenotype of an Delta elp3 mutant. We examined genetic nteractions between Delta elp3 and two other HAT mutants, Delta mst2 nd Delta gcn5 and used whole genome microarray analysis to analyze heir effects on gene expression. onclusions: Comparison of phenotypes and expression profiles in single, ouble and triple mutants indicate that these HAT enzymes have verlapping functions. Consistent with this, overlapping specificity in istone H3 acetylation is observed. However, there is no evidence for verlap with another HAT enzyme, encoded by the essential mst1(+) gene.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:sh:diva-13716 (URN)10.1186/1471-2164-11-59 (DOI)000274660300002 ()20096118 (PubMedID)2-s2.0-76949101471 (Scopus ID)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Expression profiling of S. pombe acetyltransferase identifies redundant pathways of gene regulation

Available from: 2011-12-06 Created: 2011-12-06 Last updated: 2017-07-18Bibliographically approved
4. Genome-wide characterisation of the Gcn5 histone acetyltransferase in budding yeast during stress adaptation reveals evolutionarily conserved and diverged roles
Open this publication in new window or tab >>Genome-wide characterisation of the Gcn5 histone acetyltransferase in budding yeast during stress adaptation reveals evolutionarily conserved and diverged roles
Show others...
2010 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, 200Article in journal (Refereed) Published
Abstract [en]

Background: Gcn5 is a transcriptional coactivator with histone cetyltransferase activity that is conserved with regard to structure as ell as its histone substrates throughout the eukaryotes. Gene egulatory networks within cells are thought to be evolutionarily iverged. The use of evolutionarily divergent yeast species, such as S. erevisiae and S. pombe, which can be studied under similar nvironmental conditions, provides an opportunity to examine the nterface between conserved regulatory components and their cellular pplications in different organisms. esults: We show that Gcn5 is important for a common set of stress esponses in evolutionarily diverged yeast species and that the activity f the conserved histone acetyltransferase domain is required. We define group of KCl stress response genes in S. cerevisiae that are pecifically dependent on Gcn5. Gcn5 is localised to many Gcn5-dependent enes including Gcn5 repressed targets such as FLO8. Gcn5 regulates ivergent sets of KCl responsive genes in S. cerevisiae and S. pombe. enome-wide localization studies showed a tendency for redistribution of cn5 during KCl stress adaptation in S. cerevisiae from short genes to he transcribed regions of long genes. An analogous redistribution was ot observed in S. pombe. onclusions: Gcn5 is required for the regulation of divergent sets of Cl stress-response genes in S. cerevisiae and S. pombe even though it s required a common group of stress responses, including the response o KCl. Genes that are physically associated with Gcn5 require its ctivity for their repression or activation during stress adaptation, roviding support for a role of Gcn5 as a corepressor as well as a oactivator. The tendency of Gcn5 to re-localise to the transcribed egions of long genes during KCl stress adaptation suggests that Gcn5 lays a specific role in the expression of long genes under adaptive onditions, perhaps by regulating transcriptional elongation as has been een for Gcn5 in S. pombe. Interestingly an analogous redistribution of cn5 is not seen in S. pombe. The study thus provides important new nsights in relation to why coregulators like Gcn5 are required for the orrect expression of some genes but not others.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:sh:diva-13712 (URN)10.1186/1471-2164-11-200 (DOI)000277270600002 ()20338033 (PubMedID)2-s2.0-77952260641 (Scopus ID)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Functional aspects of the Gcn5 histone acetyltransferase in stress responses of evolutionarily diverged yest species

Available from: 2011-12-06 Created: 2011-12-06 Last updated: 2017-07-18Bibliographically approved

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