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The Nucleosome as a Signal Carrying Unit: From Experimental Data to Combinatorial Models of Transcriptional Control
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik. (Komorowski)
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The human genome consists of over 3 billion nucleotides and would be around 2 meters long if uncoiled and laid out. Each human somatic cell contains all this in their nucleus which is only around 5 µm across. This extreme compaction is largely achieved by wrapping the DNA around a histone octamer, the nucleosome. Still, the DNA is accessible to the transcriptional machinery and this regulation is highly dynamic and change rapidly with, e.g. exposure to drugs. The individual histone proteins can carry specific modifications such as methylations and acetylations. These modifications are a major part of the epigenetic status of the DNA which contributes significantly to the transcriptional status of a gene - certain modifications repress transcription and others are necessary for transcription to occur. Specific histone methylations and acetylations have also been implicated in more detailed regulation such as inclusion/exclusion of individual exons, i.e. splicing. Thus, the nucleosome is involved in chromatin remodeling and transcriptional regulation – both directly from steric hindrance but also as a signaling platform via the epigenetic modifications.

In this work, we have developed tools for storage (Paper I) and normalization (Paper II) of next generation sequencing data in general, and analyzed nucleosome locations and histone modification in particular (Paper I, III and IV). The computational tools developed allowed us as one of the first groups to discover well positioned nucleosomes over internal exons in such wide spread organisms as worm, mouse and human. We have also provided biological insight into how the epigenetic histone modifications can control exon expression in a combinatorial way. This was achieved by applying a Monte Carlo feature selection system in combination with rule based modeling of exon expression. The constructed model was validated on data generated in three additional cell types suggesting a general mechanism.

 

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis , 2010. , s. 63
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 759
Emneord [en]
Next generation sequencing, Nucleosome, Histone modification, Transcriptional regulation
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
URN: urn:nbn:se:uu:diva-129181ISBN: 978-91-554-7860-5 (tryckt)OAI: oai:DiVA.org:uu-129181DiVA, id: diva2:342877
Disputas
2010-09-24, B42, BMC Building, Husargatan 3, Uppsala, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2010-09-03 Laget: 2010-08-06 Sist oppdatert: 2017-02-02bibliografisk kontrollert
Delarbeid
1. SICTIN: Rapid footprinting of massively parallel sequencing data
Åpne denne publikasjonen i ny fane eller vindu >>SICTIN: Rapid footprinting of massively parallel sequencing data
2010 (engelsk)Inngår i: BioData Mining, ISSN 1756-0381, E-ISSN 1756-0381, Vol. 3, artikkel-id 4Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND: Massively parallel sequencing allows for genome-wide hypothesis-free investigation of for instance transcription factor binding sites or histone modifications. Although nucleotide resolution detailed information can easily be generated, biological insight often requires a more general view of patterns (footprints) over distinct genomic features such as transcription start sites, exons or repetitive regions. The construction of these footprints is however a time consuming task.

METHODS: The presented software generates a binary representation of the signals enabling fast and scalable lookup. This representation allows for footprint generation in mere minutes on a desktop computer. Several different input formats are accepted, e.g. the SAM format, bed-files and the UCSC wiggle track.

CONCLUSIONS: Hypothesis-free investigation of genome wide interactions allows for biological data mining at a scale never before seen. Until recently, the main focus of analysis of sequencing data has been targeted on signal patterns around transcriptional start sites which are in manageable numbers. Today, focus is shifting to a wider perspective and numerous genomic features are being studied. To this end, we provide a system allowing for fast querying in the order of hundreds of thousands of features.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-129177 (URN)10.1186/1756-0381-3-4 (DOI)000208761100004 ()20707885 (PubMedID)
Tilgjengelig fra: 2010-08-10 Laget: 2010-08-06 Sist oppdatert: 2017-12-12bibliografisk kontrollert
2.
Posten ble ikke funnet. Det kan skyldes at posten ikke lenger er tilgjengelig eller det er feil id i adressefeltet.
3. Nucleosomes are well positioned in exons and carry characteristic histone modifications
Åpne denne publikasjonen i ny fane eller vindu >>Nucleosomes are well positioned in exons and carry characteristic histone modifications
Vise andre…
2009 (engelsk)Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, nr 10, s. 1732-1741Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The genomes of higher organisms are packaged in nucleosomes with functional histone modifications. Until now, genome-wide nucleosome and histone modification studies have focused on transcription start sites (TSSs) where nucleosomes in RNA polymerase II (RNAPII) occupied genes are well positioned and have histone modifications that are characteristic of expression status. Using public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of C. elegans. Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2 and H3K27me3 had evidently higher signal in internal exons than in the following introns and were clearly related to exon expression. These observations are suggestive of roles in splicing. Thus, exons are not only characterized by their coding capacity but also by their nucleosome organization, which seems evolutionary conserved since it is present in both primates and nematodes.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-107609 (URN)10.1101/gr.092353.109 (DOI)000270389700005 ()19687145 (PubMedID)
Merknad

De tre första författarna delar första författarskapet.

Tilgjengelig fra: 2009-08-19 Laget: 2009-08-19 Sist oppdatert: 2017-12-13bibliografisk kontrollert
4. Combinations of histone modifications control exon expression
Åpne denne publikasjonen i ny fane eller vindu >>Combinations of histone modifications control exon expression
(engelsk)Artikkel i tidsskrift (Annet vitenskapelig) Submitted
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-129178 (URN)
Tilgjengelig fra: 2010-08-10 Laget: 2010-08-06 Sist oppdatert: 2010-12-22bibliografisk kontrollert

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