Identification of Transcription Factor Binding Sites using ATAC-seq

1 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. HINT-ATAC is an open source software and available online at www.regulatory-genomics.org/hint