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Sin3: a flexible regulator of global gene expression and genome stability
Södertörn University, School of Life Sciences. Karolinska Institutet.
Södertörn University, School of Life Sciences. Karolinska Institutet.
2005 (English)In: Current Genetics, ISSN 0172-8083, E-ISSN 1432-0983, Vol. 47, no 1, 1-17 p.Article in journal (Refereed) Published
Abstract [en]

SIN3 was first identified genetically as a global regulator of transcription. Sin3 is a large protein composed mainly of protein-interaction domains, whose function is to provide structural support for a heterogeneous Sin3/histone deacetylase (HDAC) complex. The core Sin3/HDAC complex is conserved from yeast to man and consists of eight proteins. In addition to HDACs, Sin3 can sequester other enzymatic functions, including nucleosome remodeling, DNA methylation, N-acetylglucoseamine transferase activity, and histone methylation. Since the Sin3/HDAC complex lacks any DNA-binding activity, it must be targeted to gene promoters by interacting with DNA-binding proteins. Although most research on Sin3 has focused on its role as a corepressor, mounting evidence suggests that Sin3 can also positively regulate transcription. Furthermore, Sin3 is key to the propagation of epigenetically silenced domains and is required for centromere function. Thus, Sin3 provides a platform to deliver multiple combinations modifications to the chromatin, using both sequence-specific and sequence-independent mechanisms.

Place, publisher, year, edition, pages
2005. Vol. 47, no 1, 1-17 p.
National Category
Genetics
Identifiers
URN: urn:nbn:se:sh:diva-14396DOI: 10.1007/s00294-004-0541-5ISI: 000225895200001PubMedID: 15565322ScopusID: 2-s2.0-11244271837OAI: oai:DiVA.org:sh-14396DiVA: diva2:469122
Available from: 2011-12-22 Created: 2011-12-21 Last updated: 2016-12-01Bibliographically approved
In thesis
1. Histone deacetylases and their co-regulators in schizosaccharomyces pombe
Open this publication in new window or tab >>Histone deacetylases and their co-regulators in schizosaccharomyces pombe
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet, 2007. 37 p.
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-31262 (URN)978-91-7357-140-1 (ISBN)
Public defence
2007-03-23, MA636, Alfred Nobels allé 7, Huddinge, 13:00 (English)
Opponent
Supervisors
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2016-12-01Bibliographically approved

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