Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits
Background Genetic studies have provided ample evidence of the influence of non-coding DNA polymorphisms on trait variance, particularly those occurring within transcription factor binding sites. Protein binding microarrays and other platforms that can map these sites with great precision have en...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
BioMed Central Ltd.
2012
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| Online Access: | http://hdl.handle.net/1721.1/69817 |
| _version_ | 1826212604227354624 |
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| author | Wong, Daniel Teixeira, Ana Oikonomopoulos, Spyros Humburg, Peter Lone, Imtiaz N. Saliba, David Siggers, Trevor Bulyk, Martha L. Angelov, Dimitar Dimitrov, Stefan Udalova, Irina A. Ragoussis, Jiannis |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Wong, Daniel Teixeira, Ana Oikonomopoulos, Spyros Humburg, Peter Lone, Imtiaz N. Saliba, David Siggers, Trevor Bulyk, Martha L. Angelov, Dimitar Dimitrov, Stefan Udalova, Irina A. Ragoussis, Jiannis |
| author_sort | Wong, Daniel |
| collection | MIT |
| description | Background
Genetic studies have provided ample evidence of the influence of non-coding DNA polymorphisms on trait variance, particularly those occurring within transcription factor binding sites. Protein binding microarrays and other platforms that can map these sites with great precision have enhanced our understanding of how a single nucleotide polymorphism can alter binding potential within an in vitro setting, allowing for greater predictive capability of its effect on a transcription factor binding site.
Results
We have used protein binding microarrays and electrophoretic mobility shift assay-sequencing (EMSA-Seq), a deep sequencing based method we developed to analyze nine distinct human NF-κB dimers. This family of transcription factors is one of the most extensively studied, but our understanding of its DNA binding preferences has been limited to the originally described consensus motif, GGRRNNYYCC. We highlight differences between NF-κB family members and also put under the spotlight non-canonical motifs that have so far received little attention. We utilize our data to interpret the binding of transcription factors between individuals across 1,405 genomic regions laden with single nucleotide polymorphisms. We also associated binding correlations made using our data with risk alleles of disease and demonstrate its utility as a tool for functional studies of single nucleotide polymorphisms in regulatory regions.
Conclusions
NF-κB dimers bind specifically to non-canonical motifs and these can be found within genomic regions in which a canonical motif is not evident. Binding affinity data generated with these different motifs can be used in conjunction with data from chromatin immunoprecipitation-sequencing (ChIP-Seq) to enable allele-specific analyses of expression and transcription factor-DNA interactions on a genome-wide scale. |
| first_indexed | 2024-09-23T15:27:46Z |
| format | Article |
| id | mit-1721.1/69817 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:27:46Z |
| publishDate | 2012 |
| publisher | BioMed Central Ltd. |
| record_format | dspace |
| spelling | mit-1721.1/698172022-09-29T14:44:55Z Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits Wong, Daniel Teixeira, Ana Oikonomopoulos, Spyros Humburg, Peter Lone, Imtiaz N. Saliba, David Siggers, Trevor Bulyk, Martha L. Angelov, Dimitar Dimitrov, Stefan Udalova, Irina A. Ragoussis, Jiannis Harvard University--MIT Division of Health Sciences and Technology Bulyk, Martha L. Bulyk, Martha L. Background Genetic studies have provided ample evidence of the influence of non-coding DNA polymorphisms on trait variance, particularly those occurring within transcription factor binding sites. Protein binding microarrays and other platforms that can map these sites with great precision have enhanced our understanding of how a single nucleotide polymorphism can alter binding potential within an in vitro setting, allowing for greater predictive capability of its effect on a transcription factor binding site. Results We have used protein binding microarrays and electrophoretic mobility shift assay-sequencing (EMSA-Seq), a deep sequencing based method we developed to analyze nine distinct human NF-κB dimers. This family of transcription factors is one of the most extensively studied, but our understanding of its DNA binding preferences has been limited to the originally described consensus motif, GGRRNNYYCC. We highlight differences between NF-κB family members and also put under the spotlight non-canonical motifs that have so far received little attention. We utilize our data to interpret the binding of transcription factors between individuals across 1,405 genomic regions laden with single nucleotide polymorphisms. We also associated binding correlations made using our data with risk alleles of disease and demonstrate its utility as a tool for functional studies of single nucleotide polymorphisms in regulatory regions. Conclusions NF-κB dimers bind specifically to non-canonical motifs and these can be found within genomic regions in which a canonical motif is not evident. Binding affinity data generated with these different motifs can be used in conjunction with data from chromatin immunoprecipitation-sequencing (ChIP-Seq) to enable allele-specific analyses of expression and transcription factor-DNA interactions on a genome-wide scale. Wellcome Trust (London, England) (grant 075491/Z/04) European Commission (Seventh Framework Programme FP7/2007-2013: Model-In (222008)) European Commission (Seventh Framework Programme FP7 ITN Network INTEGER (214902)) Medical Research Council (Canada) (MRC project grant G0700818) 2012-03-21T20:16:59Z 2012-03-21T20:16:59Z 2011-07 2011-07 Article http://purl.org/eprint/type/JournalArticle 1465-6906 1474-7596 http://hdl.handle.net/1721.1/69817 Wong, Daniel et al. “Extensive Characterization of NF-κB Binding Uncovers Non-canonical Motifs and Advances the Interpretation of Genetic Functional Traits.” Genome Biology 12.7 (2011): R70. en_US http://dx.doi.org/10.1186/gb-2011-12-7-r70 Genome Biology Creative Commons Attribution http://creativecommons.org/licenses/by/2.0 application/pdf BioMed Central Ltd. BioMed Central |
| spellingShingle | Wong, Daniel Teixeira, Ana Oikonomopoulos, Spyros Humburg, Peter Lone, Imtiaz N. Saliba, David Siggers, Trevor Bulyk, Martha L. Angelov, Dimitar Dimitrov, Stefan Udalova, Irina A. Ragoussis, Jiannis Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits |
| title | Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits |
| title_full | Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits |
| title_fullStr | Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits |
| title_full_unstemmed | Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits |
| title_short | Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits |
| title_sort | extensive characterization of nf κb binding uncovers non canonical motifs and advances the interpretation of genetic functional traits |
| url | http://hdl.handle.net/1721.1/69817 |
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