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HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress
Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
Karolinska Intitutet.
Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
Karolinska Institutet.
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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.

Place, publisher, year, edition, pages
2009. Vol. 10, no 9, 1009-1014 p.
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:sh:diva-13886DOI: 10.1038/embor.2009.127ISI: 000269449500020PubMedID: 19633696ScopusID: 2-s2.0-69949172827OAI: oai:DiVA.org:sh-13886DiVA: diva2:465592
Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2016-09-15Bibliographically approved
In thesis
1. Characterization of Gcn5 histone acetyltransferase in Schizosaccharomyces pombe
Open this publication in new window or tab >>Characterization of Gcn5 histone acetyltransferase in Schizosaccharomyces pombe
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:nbn:se:sh:diva-30871 (URN)9789174095494 (ISBN)
Public defence
2009-08-28, 10:00
Opponent
Supervisors
Available from: 2016-09-15 Created: 2016-09-15 Last updated: 2016-09-15Bibliographically approved
2. DNA microarray approaches to understanding the regulation and evolution of gene expression networks
Open this publication in new window or tab >>DNA microarray approaches to understanding the regulation and evolution of gene expression networks
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DNA microarray technology allows biological and medical research to shift from investigation of individual functions of a few related genes to the whole genome level. This creates opportunities for discovery of complex and coordinated transcriptional networks in biological systems. The aim of this thesis has been to study gene regulation and evolution using yeast responses to environmental cues as a model system. We first developed and validated a fission yeast cDNA microarray for genome-wide expression analysis (Paper I). It is the first commercially available fission yeast microarray, which presents a useful resouce for yeast researchers and provides information required to contruct the array from scratch. Next, we characterised the gene regulatory networks involved in the pheromone response (Paper II) and investigate the role of Gcn5 transcription co-regulator, a histone acetyltransferase (HAT), in re-programming gene expression during the salt stress response in fission yeast (Paper III). We further investigated evolutionary conservation and divergence of Gcn5 in gene regulation by comparing its role in the evolutionarily distantly related yeast species. The parallel study of the fission yeast and budding yeast showed that Gcn5 has a conserved physiological role in salt stress responses, but it regulates diverged sets of stress response genes potentially via distinct mechanisms (paper IV). Finally, we investigated interactions between different HATs and between HATs and HDACs (histone deacetylases). Phenotypic studies and gene expression profiling revealed that Gcn5 has overlapping functions with another HAT, Mst2, in the stress response and DNA damage repair (Paper V). We found that the HDAC Clr3 acts antagonistically to Gcn5 in transcriptional elongation and stress responses (Paper VI).

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet, 2009. 46 p.
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-30873 (URN)978-91-7409-554-8 (ISBN)
Public defence
2009-09-29, 10:00
Available from: 2016-09-15 Created: 2016-09-15 Last updated: 2016-09-15Bibliographically approved

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