Quantitative Analysis of the DNA Methylation Sensitivity of Transcription Factor Complexes
| Autor: | Judith F. Kribelbauer, Oleg Laptenko, Siying Chen, Gabriella D. Martini, William A. Freed-Pastor, Carol Prives, Richard S. Mann, Harmen J. Bussemaker |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
transcription factors
epigenetic DNA modification 5-methyl-cytosine epigenomics high-throughput in vitro protein-DNA interaction profiling SELEX-seq tumor suppressor protein p53 human Hox protein complexes basic leucine zipper proteins bZIP integrative analysis bisulfite sequencing methylome ChIP-seq data Biology (General) QH301-705.5 |
| Zdroj: | Cell Reports, Vol 19, Iss 11, Pp 2383-2395 (2017) |
| Druh dokumentu: | article |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2017.05.069 |
| Popis: | Although DNA modifications play an important role in gene regulation, the underlying mechanisms remain elusive. We developed EpiSELEX-seq to probe the sensitivity of transcription factor binding to DNA modification in vitro using massively parallel sequencing. Feature-based modeling quantifies the effect of cytosine methylation (5mC) on binding free energy in a position-specific manner. Application to the human bZIP proteins ATF4 and C/EBPβ and three different Pbx-Hox complexes shows that 5mCpG can both increase and decrease affinity, depending on where the modification occurs within the protein-DNA interface. The TF paralogs tested vary in their methylation sensitivity, for which we provide a structural rationale. We show that 5mCpG can also enhance in vitro p53 binding and provide evidence for increased in vivo p53 occupancy at methylated binding sites, correlating with primed enhancer histone marks. Our results establish a powerful strategy for dissecting the epigenomic modulation of protein-DNA interactions and their role in gene regulation. |
| Databáze: | Directory of Open Access Journals |
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