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Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity
Södertörns högskola, Avdelning Naturvetenskap. Karolinska Institutet.
Södertörns högskola, Avdelning Naturvetenskap. Karolinska Institutet.
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2002 (Engelska)Ingår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 22, nr 7, s. 2170-2181Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Histone deacetylases (HDACs) are important for gene regulation and the maintenance of heterochromatin in eukaryotes. Schizosaccharomyces pombe was used as a model system to investigate the functional divergence within this conserved enzyme family. S. pombe has three HDACs encoded by the hda1(+), clr(3+), and clr6(+) genes. Strains mutated in these genes have previously been shown to display strikingly different phenotypes when assayed for viability, chromosome loss, and silencing. Here, conserved differences in the substrate binding pocket identify Clr6 and Hda1 as class I HDACs, while Clr3 belongs in the class II family. Furthermore, these HDACs were shown to have strikingly different subcellular localization patterns. Hda1 was localized to the cytoplasm, while most of Clr3 resided throughout the nucleus. Finally, Clr6 was localized exclusively on the chromosomes in a spotted pattern. Interestingly, Clr3, the only HDAC present in the nucleolus, was required for ribosomal DNA (rDNA) silencing. Clr3 presumably acts directly on heterochromatin, since it colocalized with the centromere, mating-type region, and rDNA as visualized by in situ hybridization. In addition, Clr3 could be cross-linked to mat3 in chromatin immunoprecipitation experiments. Western analysis of bulk histone preparations indicated that Hda1 (class I) had a generally low level of activity in vivo and Clr6 (class 1) had a high level of activity and broad in vivo substrate specificity, whereas Clr3 (class II) displayed its main activity on acetylated lysine 14 of histone H3. Thus, the distinct functions of the S. pombe HDACs are likely explained by their distinct cellular localization and their different in vivo specificities.

Ort, förlag, år, upplaga, sidor
2002. Vol. 22, nr 7, s. 2170-2181
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
URN: urn:nbn:se:sh:diva-15808DOI: 10.1128/MCB.22.7.2170-2181.2002ISI: 000174407500020PubMedID: 11884604Scopus ID: 2-s2.0-0036122494OAI: oai:DiVA.org:sh-15808DiVA, id: diva2:508342
Tillgänglig från: 2012-03-08 Skapad: 2012-03-07 Senast uppdaterad: 2017-07-20Bibliografiskt granskad
Ingår i avhandling
1. Histone deacetylases and their co-regulators in schizosaccharomyces pombe
Öppna denna publikation i ny flik eller fönster >>Histone deacetylases and their co-regulators in schizosaccharomyces pombe
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The DNA in every eukaryotic cell is wrapped around eight core histones to form the nucleosome. Therefore all events that involve DNA must also involve chromatin and nucleosomes. By regulating chromatin structure the cell can regulate the reactivity of the DNA. One of the most common ways of altering nucleosomes is the acetylation of lysine residues. Two enzymes are required to maintain the correct equilibrium for optimal cell growth: histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs). In general, histone hypoacetylation is correlated with transcriptional inactivation, while hyperacetylation is correlated with active gene transcription. In Schizosaccharomyces pombe, mating type loci are silenced. Deletion of HDAC Hos2 had previously been shown to slightly increase silencing at the mating type locus. To assess whether any other HDAC was necessary for mating type silencing, cells were treated with HDAC poison Trichostatin A (TSA). TSA was found to cause a mild derepression of the mating type locus, indicating that another HDAC was responsible for silencing in this region. The RNA interference nuclease Dcr1 was later identified, and showed to degrade double stranded RNA into small nucleotide fragments. Deletion of dcr1 caused chromosome segregation defects and derepression of centromeric silencing. Rpd3 in S. cerevisiae is recruited to genomic targets by interacting with co-regulator Sin3. S. pombe has three Sin3 homologs. Pst1 interacts with the HDAC Clr6, and like Clr6 is an essential gene, mutants of which display chromosome mis-segregation and derepression of centromeric silencing. Pst1 was required for centromeric cohesion, and localized to centromeres in late S phase. Thus a co-repressor paradigm could be applied to centromere silencing as well. A comparative characterization of HDACs in S. pombe showed that the HDACs had different localizations and histone specificities. The comparison of HDACs was taken further with a genome wide expression analysis and histone density study of mutants. Results indicated that Clr6 was most often involved in promoter initiated gene repression, whereas Hos2 promoted the high expression of growth related genes by deacetylating H4K16ac in their coding regions. A class II HDAC, Clr3, was found to act cooperatively with Sir2 throughout the genome. Using a genomic approach to analyze Pst3, it was established that Clr6 and Pst3 could cooperate to negatively regulate genes by binding to their promoter regions. On the other hand, Pst3 was also involved in the up-regulation of ribosome biosynthesis genes, and could bind to the rDNA.

Ort, förlag, år, upplaga, sidor
Stockholm: Karolinska Institutet, 2007. s. 37
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:sh:diva-31262 (URN)978-91-7357-140-1 (ISBN)
Disputation
2007-03-23, MA636, Alfred Nobels allé 7, Huddinge, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-12-01 Skapad: 2016-12-01 Senast uppdaterad: 2016-12-01Bibliografiskt granskad

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Bjerling, PernillaSilverstein, Rebecca AEkwall, Karl

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