The CHD chromatin remodeling factors in Schizosaccharomyces pombe
Author: Walfridsson, Julian
Date: 2007-03-16
Location: Sal MA 636, Moas Båge, Södertörns Högskola, Alfred Nobels allé 7, Huddinge
Time: 09.00
Department: Biovetenskaper och näringslära / Biosciences and Nutrition
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thesis.pdf (1.843Mb)
Abstract
Regulation of chromatin structure is essential in a wide variety of
processes including transcriptional regulation, recombination,
replication, chromosome segregation, development and differentiation. The
enzymes that are central in regulating chromatin structure can be
classified into two major groups. The first group of proteins consists of
the histone modifying enzymes that catalyse the addition or removal of
posttranslational modifications of histones. The second group of proteins
is the highly conserved ATP-dependent remodeling factors that modify the
nucleosome structure. Evidence is emerging that these two groups of
proteins are intimately linked in chromatin function.
This thesis describes the roles of the S. pombe Hrp1 and Hrp3 CHD
remodeling factors in chromatin regulation, which have been shown to be
important in centromere function and transcriptional regulation. The Hrp
remodeling factors are functionally linked to the histone chaperone Nap1
as well as acetylation and methylation activities. We have demonstrated
that Hrp1 has both independent and overlapping roles with Hrp3 in
regulating centromere assembly and function. Both hrp1 and hrp3 deficient
cells are disrupted in centromere silencing and display various
chromosome segregation defects indicative of functions at both the outer
repeats and the central core of the centromere. These phenotypes are
likely to originate from the requirement of Hrp1 in keeping the
centromeres hypoacetylated and for maintaining the histone H3 variant
CENP-A at the central core of the centromere. Genetic interactions
combined with chromatin immunoprecipitation and fluorescent in situ
hybridisation indicate that Hrp1 stimulates CENP-A assembly during DNA
replication.
In addition to their centromere functions, the Hrp remodeling factors
contribute to transcriptional regulation by promoting histone removal.
Biochemical purifications identified a physical interaction between Hrp1
and Hrp3 and with the histone chaperone Nap1. Consistent with the
physical interaction data, genome wide analysis showed that the CHD
remodeling factors together with Nap1 have a common function in removing
histones particularly at promoter regions. Interestingly, we found that
histone disassembly in coding regions by both Hrp1 and Hrp3 promote
transcriptional activation. Cell synchronisation studies revealed that
the Hrp1 dependent histone disassembly occurs in a DNA replication
independent manner. A functional interaction between acetylation and
remodeling activity was established based on the high degree of overlap
between the Hrp ATPases, regions affected by Nap1 histone density, and
corresponding histone deacetylase and histone acetylase targets.
Finally, we discovered that regions with upregulated genes and altered
levels of histone modifications in the HDAC clr6-1 mutant were
significantly similar to equivalent lists for the histone demethyl
transferase swm1 mutant. In addition, the same regions with upregulated
genes and effects on histone modification levels in the swm1 and clr6
mutant overlapped with Hrp1 and Hrp3 binding targets. Thus, it is likely
that Swm1 act in concert with Clr6 and Hrp1 to mediate transcriptional
silencing.
Thus, HDACs, HATs, and HMTs are intimately linked in vivo to CHD
nucleosome remodeling factors as well as histone chaperones in centromere
assembly and transcriptional regulation.
List of papers:
I. Walfridsson J, Bjerling P, Thalen M, Yoo EJ, Park SD, Ekwall K (2005). "The CHD remodeling factor Hrp1 stimulates CENP-A loading to centromeres." Nucleic Acids Res 33(9): 2868-79. Print 2005
Pubmed
II. 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
III. Walfridsson J, Khorosjutina O, Gustafsson CM, Ekwall K (2007). "A genome wide role for CHD remodeling factors and Nap1 in nucleosome disassembly." (Manuscript)
IV. Opel M, Lando D, Bonilla C, Trewick SC, Boukaba A, Walfridsson J, Cauwood J, Werler PJH, Carr AM, Kouzarides T, Murzina NV, Allshire RC, Ekwall K, Laue ED (2007). "Genome-wide studies of histone demethylation catalysed by the fission yeast homologues of mammalian LSD1." (Manuscript)
I. Walfridsson J, Bjerling P, Thalen M, Yoo EJ, Park SD, Ekwall K (2005). "The CHD remodeling factor Hrp1 stimulates CENP-A loading to centromeres." Nucleic Acids Res 33(9): 2868-79. Print 2005
Pubmed
II. 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
III. Walfridsson J, Khorosjutina O, Gustafsson CM, Ekwall K (2007). "A genome wide role for CHD remodeling factors and Nap1 in nucleosome disassembly." (Manuscript)
IV. Opel M, Lando D, Bonilla C, Trewick SC, Boukaba A, Walfridsson J, Cauwood J, Werler PJH, Carr AM, Kouzarides T, Murzina NV, Allshire RC, Ekwall K, Laue ED (2007). "Genome-wide studies of histone demethylation catalysed by the fission yeast homologues of mammalian LSD1." (Manuscript)
Issue date: 2007-02-23
Rights:
Publication year: 2007
ISBN: 978-91-7357-106-7
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