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Different distribution of histone modifications in genes with unidirectional and bidirectional transcription and a role of CTCF and cohesin in directing transcription
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
2015 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, 300Article in journal (Refereed) Published
Abstract [en]

Background: Several post-translational histone modifications are mainly found in gene promoters and are associated with the promoter activity. It has been hypothesized that histone modifications regulate the transcription, as opposed to the traditional view with transcription factors as the key regulators. Promoters of most active genes do not only initiate transcription of the coding sequence, but also a substantial amount of transcription of the antisense strand upstream of the transcription start site (TSS). This promoter feature has generally not been considered in previous studies of histone modifications and transcription factor binding.

Results: We annotated protein-coding genes as bi- or unidirectional depending on their mode of transcription and compared histone modifications and transcription factor occurrences between them. We found that H3K4me3, H3K9ac, and H3K27ac were significantly more enriched upstream of the TSS in bidirectional genes compared with the unidirectional ones. In contrast, the downstream histone modification signals were similar, suggesting that the upstream histone modifications might be a consequence of transcription rather than a cause. Notably, we found well-positioned CTCF and RAD21 peaks approximately 60-80 bp upstream of the TSS in the unidirectional genes. The peak heights were related to the amount of antisense transcription and we hypothesized that CTCF and cohesin act as a barrier against antisense transcription.

Conclusions: Our results provide insights into the distribution of histone modifications at promoters and suggest a novel role of CTCF and cohesin as regulators of transcriptional direction.

Place, publisher, year, edition, pages
2015. Vol. 16, 300
Keyword [en]
Antisense transcription, CTCF, RAD21, Cohesin, CAGE, Epigenetics, Transcription factor, Histone modification
National Category
Bioinformatics and Systems Biology
Identifiers
URN: urn:nbn:se:uu:diva-230158DOI: 10.1186/s12864-015-1485-5ISI: 000355166000001PubMedID: 25881024OAI: oai:DiVA.org:uu-230158DiVA: diva2:739031
Available from: 2014-08-19 Created: 2014-08-19 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Rule-based Models of Transcriptional Regulation and Complex Diseases: Applications and Development
Open this publication in new window or tab >>Rule-based Models of Transcriptional Regulation and Complex Diseases: Applications and Development
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As we gain increased understanding of genetic disorders and gene regulation more focus has turned towards complex interactions. Combinations of genes or gene and environmental factors have been suggested to explain the missing heritability behind complex diseases. Furthermore, gene activation and splicing seem to be governed by a complex machinery of histone modification (HM), transcription factor (TF), and DNA sequence signals. This thesis aimed to apply and develop multivariate machine learning methods for use on such biological problems. Monte Carlo feature selection was combined with rule-based classification to identify interactions between HMs and to study the interplay of factors with importance for asthma and allergy.

Firstly, publicly available ChIP-seq data (Paper I) for 38 HMs was studied. We trained a classifier for predicting exon inclusion levels based on the HMs signals. We identified HMs important for splicing and illustrated that splicing could be predicted from the HM patterns. Next, we applied a similar methodology on data from two large birth cohorts describing asthma and allergy in children (Paper II). We identified genetic and environmental factors with importance for allergic diseases which confirmed earlier results and found candidate gene-gene and gene-environment interactions.

In order to interpret and present the classifiers we developed Ciruvis, a web-based tool for network visualization of classification rules (Paper III). We applied Ciruvis on classifiers trained on both simulated and real data and compared our tool to another methodology for interaction detection using classification. Finally, we continued the earlier study on epigenetics by analyzing HM and TF signals in genes with or without evidence of bidirectional transcription (Paper IV). We identified several HMs and TFs with different signals between unidirectional and bidirectional genes. Among these, the CTCF TF was shown to have a well-positioned peak 60-80 bp upstream of the transcription start site in unidirectional genes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1167
Keyword
Histone modification, Transcription factor, Transcriptional regulation, Next-generation sequencing, Feature selection, Machine learning, Rule-based classification, Asthma, Allergy
National Category
Bioinformatics and Systems Biology Bioinformatics (Computational Biology)
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-230159 (URN)978-91-554-9005-8 (ISBN)
Public defence
2014-10-03, BMC C8:301, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2014-09-12 Created: 2014-08-19 Last updated: 2015-01-22

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Bornelöv, SusanneKomorowski, JanWadelius, Claes

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