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Improving the detection of transcription factor binding regions Hunt, Christine Rebecca
Abstract
The identification of non-coding regulatory elements in the genome has been the focus of much experimental and computational effort. However, both experimental data, such as ChIP-seq, and computational methods of transcription factor (TF) binding predictions suffer from a degree of non-specificity. ChIP-seq experiments report regions that don’t contain the expected canonical motif for the ChIPped TF, which may arise from indirect binding or a non-TF-specific mechanism. Computational predictions based on sequence-level information alone are plagued by false positives. This thesis explores computational approaches to improve both the interpretation of large-scale TF binding data, and the detection of TF binding regions. In Chapters 2 and 3 we observe that experimentally defined regulatory regions of the human genome are a mixture of sub-groups reflecting distinct properties. On average a third of a ChIP-seq dataset does not contain the targeted TF’s motif, and within this subset up to 45% of the ChIP-seq peaks are unexpectedly enriched for a small class of non-targeted TFs’ motifs. Many of these regions are not specific to a TF but are ChIPped by multiple diverse TFs across multiple cell types. These recurring regions tend to be the lower scoring peaks of a dataset, are less likely to reproduce between experimental replicates, and tend to associate with cohesin and polycomb protein occupied positions in the genome. The regulatory regions with a greater specificity for a TF do not share these properties. Based on these observations we suggest a TF ‘loading-zone’ model to account for the presence of the aforementioned recurrent regions in ChIP-seq data. In Chapter 4 we further explore the regulatory region subgroups with a biophysical simulator of TF occupancy (tfOS). Within tfOS we have incorporated TF-DNA interaction energies, TF search mechanics, cooperative TF interactions, and sequence accessibility data into the model. Simulations with tfOS across sequences reveal distinct features associated with recurrent and non-recurrent regions described in Chapter 3. The research presented has improved our understanding and interpretation of large-scale TF binding data and advanced our understanding of TF regulatory regions, leading to improved annotation and interpretation of the human genome.
Item Metadata
Title |
Improving the detection of transcription factor binding regions
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2014
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Description |
The identification of non-coding regulatory elements in the genome has been the focus of much experimental and computational effort. However, both experimental data, such as ChIP-seq, and computational methods of transcription factor (TF) binding predictions suffer from a degree of non-specificity. ChIP-seq experiments report regions that don’t contain the expected canonical motif for the ChIPped TF, which may arise from indirect binding or a non-TF-specific mechanism. Computational predictions based on sequence-level information alone are plagued by false positives. This thesis explores computational approaches to improve both the interpretation of large-scale TF binding data, and the detection of TF binding regions.
In Chapters 2 and 3 we observe that experimentally defined regulatory regions of the human genome are a mixture of sub-groups reflecting distinct properties. On average a third of a ChIP-seq dataset does not contain the targeted TF’s motif, and within this subset up to 45% of the ChIP-seq peaks are unexpectedly enriched for a small class of non-targeted TFs’ motifs. Many of these regions are not specific to a TF but are ChIPped by multiple diverse TFs across multiple cell types. These recurring regions tend to be the lower scoring peaks of a dataset, are less likely to reproduce between experimental replicates, and tend to associate with cohesin and polycomb protein occupied positions in the genome. The regulatory regions with a greater specificity for a TF do not share these properties. Based on these observations we suggest a TF ‘loading-zone’ model to account for the presence of the aforementioned recurrent regions in ChIP-seq data.
In Chapter 4 we further explore the regulatory region subgroups with a biophysical simulator of TF occupancy (tfOS). Within tfOS we have incorporated TF-DNA interaction energies, TF search mechanics, cooperative TF interactions, and sequence accessibility data into the model. Simulations with tfOS across sequences reveal distinct features associated with recurrent and non-recurrent regions described in Chapter 3.
The research presented has improved our understanding and interpretation of large-scale TF binding data and advanced our understanding of TF regulatory regions, leading to improved annotation and interpretation of the human genome.
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Genre | |
Type | |
Language |
eng
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Date Available |
2014-12-12
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivs 2.5 Canada
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DOI |
10.14288/1.0166083
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Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2015-02
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
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DSpace
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Attribution-NonCommercial-NoDerivs 2.5 Canada