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Genome-Wide Studies of Histone Demethylation Catalysed by the Fission Yeast Homologues of Mammalian LSD1
University of Cambridge, Cambridge, United Kingdom.
Gurdon Institute and Department of Pathology, Cambridge, United Kingdom.
Södertörn University, School of Life Sciences. Karolinska Institutet.
University of Edinburgh, Edinburgh, United Kingdom.
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2007 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 2, no 4, e386Article in journal (Refereed) Published
Abstract [en]

In order to gain a more global view of the activity of histone demethylases, we report here genome-wide studies of the fission yeast SWIRM and polyamine oxidase (PAO) domain homologues of mammalian LSD1. Consistent with previous work we find that the two S. pombe proteins, which we name Swm1 and Swm2 (after SWIRM1 and SWIRM2), associate together in a complex. However, we find that this complex specifically demethylates lysine 9 in histone H3 (H3K9) and both up-and down-regulates expression of different groups of genes. Using chromatin-immunoprecipitation, to isolate fragments of chromatin containing either H3K4me2 or H3K9me2, and DNA microarray analysis (ChIP-chip), we have studied genome-wide changes in patterns of histone methylation, and their correlation with gene expression, upon deletion of the swm1(+) gene. Using hyper-geometric probability comparisons we uncover genetic links between lysine-specific demethylases, the histone deacetylase Clr6, and the chromatin remodeller Hrp1. The data presented here demonstrate that in fission yeast the SWIRM/PAO domain proteins Swm1 and Swm2 are associated in complexes that can remove methyl groups from lysine 9 methylated histone H3. In vitro, we show that bacterially expressed Swm1 also possesses lysine 9 demethylase activity. In vivo, loss of Swm1 increases the global levels of both H3K9me2 and H3K4me2. A significant accumulation of H3K4me2 is observed at genes that are up-regulated in a swm1 deletion strain. In addition, H3K9me2 accumulates at some genes known to be direct Swm1/2 targets that are down-regulated in the swm1 Delta strain. The in vivo data indicate that Swm1 acts in concert with the HDAC Clr6 and the chromatin remodeller Hrp1 to repress gene expression. In addition, our in vitro analyses suggest that the H3K9 demethylase activity requires an unidentified post-translational modification to allow it to act. Thus, our results highlight complex interactions between histone demethylase, deacetylase and chromatin remodelling activities in the regulation of gene expression.

Place, publisher, year, edition, pages
2007. Vol. 2, no 4, e386
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:sh:diva-14229DOI: 10.1371/journal.pone.0000386ISI: 000207445500016OAI: oai:DiVA.org:sh-14229DiVA: diva2:467803
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2016-12-29Bibliographically approved
In thesis
1. The CHD chromatin remodeling factors in schizosaccharomyces pombe
Open this publication in new window or tab >>The CHD chromatin remodeling factors in schizosaccharomyces pombe
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Stockholm: Karolinska instiutet, 2007. 73 p.
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-31557 (URN)978-91-7357-106-7 (ISBN)
Public defence
2007-03-16, MA636, Moas Båge, Huddinge, 09:00 (English)
Opponent
Supervisors
Available from: 2016-12-29 Created: 2016-12-29 Last updated: 2016-12-29Bibliographically approved

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Publisher's full texthttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1849891/

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