Journal
CELL REPORTS
Volume 19, Issue 11, Pages 2383-2395Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.069
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Funding
- Howard Hughes Medical Institute International Student Research Fellowship
- NIH [R01HG003008, R35GM118336, P01CA087497, R01CA196234, G20RR030893]
- NYSTAR [C090171]
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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 ((5)mC) on binding free energy in a position- specific manner. Application to the human bZIP proteins ATF4 and C/EBPb and three different Pbx-Hox complexes shows that 5 mCpG can both increase and decrease affinity, depending on where the modification occurs within the protein-DNAinterface. The TF paralogs tested vary in their methylation sensitivity, for which we provide a structural rationale. We show that 5 mCpG 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.
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