Wellington: a novel method for the accurate identification of digital genomic footprints from DNase-seq data.
The expression of eukaryotic genes is regulated by cis-regulatory elements such as promoters and enhancers, which bind sequence-specific DNA-binding proteins. One of the great challenges in the gene regulation field is to characterise these elements. This involves the identification of transcription factor (TF) binding sites within regulatory elements that are occupied in a defined regulatory context. Digestion with DNase and the subsequent analysis of regions protected from cleavage (DNase footprinting) has for many years been used to identify specific binding sites occupied by TFs at individual cis-elements with high resolution. This methodology has recently been adapted for high-throughput sequencing (DNase-seq). In this study, we describe an imbalance in the DNA strand-specific alignment information of DNase-seq data surrounding protein-DNA interactions that allows accurate prediction of occupied TF binding sites. Our study introduces a novel algorithm, Wellington, which considers the imbalance in this strand-specific information to efficiently identify DNA footprints. This algorithm significantly enhances specificity by reducing the proportion of false positives and requires significantly fewer predictions than previously reported methods to recapitulate an equal amount of ChIP-seq data. We also provide an open-source software package, pyDNase, which implements the Wellington algorithm to interface with DNase-seq data and expedite analyses.
Warwick Systems Biology Centre, University of Warwick, Coventry, CV4 7AL, United Kingdom, School of Cancer Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom, Department of Statistics, University of Warwick, Coventry, CV4 7AL, United Kingdom and School of Immunity and Infection, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
Jason
J
Piper
Markus C
MC
Elze
Pierre
P
Cauchy
Peter N
PN
Cockerill
Constanze
C
Bonifer
Sascha
S
Ott
D000465:Algorithms; D001665:Binding Sites; D018983:DNA Footprinting / Q000379:methods*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003851:Deoxyribonucleases; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017422:Sequence Analysis, DNA; D012984:Software; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D014157:Transcription Factors; D003851:Deoxyribonucleases