02302nas a2200157   4500008004100000022001400041245008500055210006900140260000800209300001400217490000700231520174700238100002001985700002402005856011502029       2021                        eng d  a1367-480300aResolving diverse protein-DNA footprints from exonuclease-based ChIP experiments0 aResolving diverse proteinDNA footprints from exonucleasebased Ch  cJUL  aI367-I3750 v373 aMotivation: High-throughput chromatin immunoprecipitation (ChIP) sequencing-based assays capture genomic regions associated with the profiled transcription factor (TF). ChIP-exo is a modified protocol, which uses lambda exonuclease to digest DNA close to the TF-DNA complex, in order to improve on the positional resolution of the TF-DNA contact. Because the digestion occurs in the 50-30 orientation, the protocol produces directional footprints close to the complex, on both sides of the double stranded DNA. Like all ChIP-based methods, ChIP-exo reports a mixture of different regions associated with the TF: those bound directly to the TF as well as via intermediaries. However, the distribution of footprints are likely to be indicative of the complex forming at the DNA. Results: We present ExoDiversity, which uses a model-based framework to learn a joint distribution over footprints and motifs, thus resolving the mixture of ChIP-exo footprints into diverse binding modes. It uses no prior motif or TF information and automatically learns the number of different modes from the data. We show its application on a wide range of TFs and organisms/cell-types. Because its goal is to explain the complete set of reported regions, it is able to identify co-factor TF motifs that appear in a small fraction of the dataset. Further, ExoDiversity discovers small nucleotide variations within and outside canonical motifs, which co-occur with variations in footprints, suggesting that the TF-DNA structural configuration at those regions is likely to be different. Finally, we show that detected modes have specific DNA shape features and conservation signals, giving insights into the structure and function of the putative TF-DNA complexes.1 aBiswas, Anushua1 aNarlikar, Leelavati  uhttps://library.ncl.res.in/content/resolving-diverse-protein-dna-footprints-exonuclease-based-chip-experiments