Identification of Transcription Factor Binding Sites using ATAC-seq

Transposase-Accessible Chromatin (ATAC) followed by sequencing (ATAC-seq) is a simple and fast protocol for detection of open chromatin. However, computational footprinting in ATAC-seq, i.e. search for regions with depletion of cleavage events due to transcription factor binding sites, has been poorly explored so far. We propose HINT-ATAC, a footprinting method that addresses ATAC- seq specific protocol artifacts. HINT-ATAC uses a probabilistic framework based on Variable-order Markov models to learn the complex sequence cleavage preferences of the transposase enzyme. Moreover, we observed specific strand-specific cleavage patterns around the binding sites of transcription factors, which are determined by local nucleosome architecture. HINT-ATAC explores local nucleosome architecture to significantly outperform competing footprinting methods in predicting transcription factor binding sites by ChIP-seq.