A long-term goal of my lab is to understand how naturally occurring genetic and epigenetic variation in the genome gives rise to genome-wide variation in transcription factor-DNA interactions, and how these variation collectively alter the regulatory networks in the cell. To this end we are utilizing both “dry”- and “wet”-lab genomics methods to investigate the effect of natural variation in protein-DNA interaction using the diverse genomes and epigenomes of natural strains (accessions) of Arabidopsis thaliana as model. We developed the DNA affinity purification-sequencing (DAP-seq) technique that allows efficient and accurate mapping of genome-wide binding sites in endogenous genome context for hundreds of transcription factors. Using DAP-seq we are systematically characterizing the variation in genome-wide transcription factor binding sites across multiple accessions, between coding variants of transcription factors, and between variable transcription factor complexes. We are creating computational models to analyze the experimentally determined binding site variation to understand the contributions from sequence and non-sequence features of endogenous genomic DNA, providing important baseline datasets for studying in vivo binding variation. In collaboration with multiple groups we are applying DAP-seq to agriculturally and ecologically important plants including maize, grapevine, and poplars.