Accurate and sensitive quantification of protein-DNA binding affinity.

作者: Chaitanya Rastogi , H. Tomas Rube , Judith F. Kribelbauer , Justin Crocker , Ryan E. Loker

DOI: 10.1073/PNAS.1714376115

关键词: Transcription factorDNA footprintingBinding siteEnhancer bindingGeneGeneticsElectrophoretic mobility shift assayBiologyGenomic libraryDNA binding site

摘要: Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations TF sites are increasingly found be associated with human disease, yet we currently lack robust methods predict these sites. Here, developed versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers biophysical model of protein-DNA recognition across the full affinity range from library vitro selected NRLB predicts Max homodimer near-perfect agreement existing low-throughput measurements. It can capture specificity p53 tetramer and distinguish multiple modes within single sample. Additionally, confirm newly identified low-affinity enhancer functional vivo, their contribution matches predicted affinity. Our results establish powerful paradigm for identifying protein interpreting regulatory sequences eukaryotic genomes.

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