Universal correction of enzymatic sequence bias reveals molecular signatures of protein/DNA interactions

André L Martins, Ninad M Walavalkar, Warren D Anderson, Chongzhi Zang, Michael J Guertin
<span title="2017-11-08">2017</span> <i title="Oxford University Press (OUP)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/hfp6p6inqbdexbsu4r7usndpte" style="color: black;">Nucleic Acids Research</a> </i> &nbsp;
Coupling molecular biology to high-throughput sequencing has revolutionized the study of biology. Molecular genomics techniques are continually refined to provide higher resolution mapping of nucleic acid interactions and structure. Sequence preferences of enzymes can interfere with the accurate interpretation of these data. We developed seqOutBias to characterize enzymatic sequence bias from experimental data and scale individual sequence reads to correct intrinsic enzymatic sequence biases.
more &raquo; ... -qOutBias efficiently corrects DNase-seq, TACh-seq, ATAC-seq, MNase-seq and PRO-seq data. We show that seqOutBias correction facilitates identification of true molecular signatures resulting from transcription factors and RNA polymerase interacting with DNA. Enzymatic sequence biases are most well-characterized for DNase-seq experiments (10-12), but nearly all molecular genomics experiments employ enzymatic treatments and these enzymes also have intrinsic biases. Herein, we show that DNase, Cyanase, Benzonase, MNase, Tn5 transposase and T4 RNA ligase all exhibit sequence preferences that are effectively corrected with seqOutBias. We also characterize enzymatic bias that results from T4 DNA Polymerase, T4 Polynucleotide Kinase and Klenow Fragment (3'→5' exo-) treatment of DNA in preparation of high-throughput sequencing libraries. At last, we show that correction of enzymatic sequence bias highlights true molecular signatures, such as sharp peaks of hypersensitivity and footprints, that result from protein/DNA interactions.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1093/nar/gkx1053">doi:10.1093/nar/gkx1053</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/29126307">pmid:29126307</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC5778497/">pmcid:PMC5778497</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/ci2nlk4scrbphc43hzxrp2vfae">fatcat:ci2nlk4scrbphc43hzxrp2vfae</a> </span>
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