Histone deacetylases and their co-regulators in Schizosaccharomyces pombe
Author: Silverstein, Rebecca Ann
Date: 2007-03-23
Location: Sal MA636, Moas Båge, Södertörns Högskola, Alfred Nobels allé 7, Huddinge
Time: 13.00
Department: Biovetenskaper och näringslära / Biosciences and Nutrition
View/ Open:
thesis.pdf (1.847Mb)
Abstract
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.
List of papers:
I. Olsson TG, Silverstein RA, Ekwall K, Sunnerhagen P (1999). "Transient inhibition of histone deacetylase activity overcomes silencing in the mating-type region in fission yeast." Curr Genet 35(2): 82-7
Pubmed
II. Provost P, Silverstein RA, Dishart D, Walfridsson J, Djupedal I, Kniola B, Wright A, Samuelsson B, Radmark O, Ekwall K (2002). "Dicer is required for chromosome segregation and gene silencing in fission yeast cells." Proc Natl Acad Sci U S A 99(26): 16648-53. Epub 2002 Dec 13
Pubmed
III. Silverstein RA, Richardson W, Levin H, Allshire R, Ekwall K (2003). "A new role for the transcriptional corepressor SIN3; regulation of centromeres." Curr Biol 13(1): 68-72
Pubmed
IV. Bjerling P, Silverstein RA, Thon G, Caudy A, Grewal S, Ekwall K (2002). "Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity." Mol Cell Biol 22(7): 2170-81
Pubmed
V. Wiren M, Silverstein RA, Sinha I, Walfridsson J, Lee HM, Laurenson P, Pillus L, Robyr D, Grunstein M, Ekwall K (2005). "Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast." EMBO J 24(16): 2906-18. Epub 2005 Aug 4
Pubmed
VI. Silverstein RA, Walfridsson J, Bonilla C, Ekwall K (2007). "Sin3 homolog Pst3 a key factor in nucleolar function." Current Biology (Submitted)
I. Olsson TG, Silverstein RA, Ekwall K, Sunnerhagen P (1999). "Transient inhibition of histone deacetylase activity overcomes silencing in the mating-type region in fission yeast." Curr Genet 35(2): 82-7
Pubmed
II. Provost P, Silverstein RA, Dishart D, Walfridsson J, Djupedal I, Kniola B, Wright A, Samuelsson B, Radmark O, Ekwall K (2002). "Dicer is required for chromosome segregation and gene silencing in fission yeast cells." Proc Natl Acad Sci U S A 99(26): 16648-53. Epub 2002 Dec 13
Pubmed
III. Silverstein RA, Richardson W, Levin H, Allshire R, Ekwall K (2003). "A new role for the transcriptional corepressor SIN3; regulation of centromeres." Curr Biol 13(1): 68-72
Pubmed
IV. Bjerling P, Silverstein RA, Thon G, Caudy A, Grewal S, Ekwall K (2002). "Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity." Mol Cell Biol 22(7): 2170-81
Pubmed
V. Wiren M, Silverstein RA, Sinha I, Walfridsson J, Lee HM, Laurenson P, Pillus L, Robyr D, Grunstein M, Ekwall K (2005). "Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast." EMBO J 24(16): 2906-18. Epub 2005 Aug 4
Pubmed
VI. Silverstein RA, Walfridsson J, Bonilla C, Ekwall K (2007). "Sin3 homolog Pst3 a key factor in nucleolar function." Current Biology (Submitted)
Issue date: 2007-03-02
Rights:
Publication year: 2007
ISBN: 978-91-7357-140-1
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