Quantitative Analysis of the DNA Methylation Sensitivity of Transcription Factor Complexes
| Autor: | Gabriella Martini, Carol Prives, Richard S. Mann, Siying Chen, Oleg Laptenko, William A. Freed-Pastor, Judith F. Kribelbauer, Harmen J. Bussemaker |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
DNA--Methylation tumor suppressor protein p53 methylome ChIP-seq data SELEX-seq DNA-protein interactions General Biochemistry Genetics and Molecular Biology Article Epigenesis Genetic 5-methyl-cytosine 03 medical and health sciences human Hox protein complexes Epigenetics of physical exercise transcription factors bZIP Humans Methylated DNA immunoprecipitation Epigenetics epigenetic DNA modification Enhancer lcsh:QH301-705.5 Epigenomics Regulation of gene expression Genetic regulation basic leucine zipper proteins biology DNA Methylation Molecular biology Cell biology 030104 developmental biology Histone Gene Expression Regulation lcsh:Biology (General) DNA methylation epigenomics biology.protein bisulfite sequencing high-throughput in vitro protein-DNA interaction profiling Protein Binding integrative analysis |
| Zdroj: | Cell Reports, Vol 19, Iss 11, Pp 2383-2395 (2017) |
| ISSN: | 2211-1247 |
| 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: | OpenAIRE |
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