Inferring Direct DNA Binding From ChIP-seq

Nucleic Acids Res. 2012 Sep 1;40(17):e128. doi: 10.1093/nar/gks433. Epub 2012 May 18.

Abstract

Genome-wide binding data from transcription factor ChIP-seq experiments is the best source of information for inferring the relative DNA-binding affinity of these proteins in vivo. However, standard motif enrichment analysis and motif discovery approaches sometimes fail to correctly identify the binding motif for the ChIP-ed factor. To overcome this problem, we propose 'central motif enrichment analysis' (CMEA), which is based on the observation that the positional distribution of binding sites matching the direct-binding motif tends to be unimodal, well centered and maximal in the precise center of the ChIP-seq peak regions. We describe a novel visualization and statistical analysis tool--CentriMo--that identifies the region of maximum central enrichment in a set of ChIP-seq peak regions and displays the positional distributions of predicted sites. Using CentriMo for motif enrichment analysis, we provide evidence that one transcription factor (Nanog) has different binding affinity in vivo than in vitro, that another binds DNA cooperatively (E2f1), and confirm the in vivo affinity of NFIC, rescuing a difficult ChIP-seq data set. In another data set, CentriMo strongly suggests that there is no evidence of direct DNA binding by the ChIP-ed factor (Smad1). CentriMo is now part of the MEME Suite software package available at http://meme.nbcr.net. All data and output files presented here are available at: http://research.imb.uq.edu.au/t.bailey/sd/Bailey2011a.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Animals
  • Binding Sites
  • Chromatin Immunoprecipitation*
  • E2F1 Transcription Factor / metabolism
  • Embryonic Stem Cells / metabolism
  • High-Throughput Nucleotide Sequencing*
  • Homeodomain Proteins / metabolism
  • Mice
  • Nanog Homeobox Protein
  • Nucleotide Motifs
  • Position-Specific Scoring Matrices
  • Regulatory Elements, Transcriptional*
  • Sequence Analysis, DNA
  • Smad1 Protein / metabolism
  • Software*
  • Transcription Factors / metabolism*

Substances

  • E2F1 Transcription Factor
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Smad1 Protein
  • Smad1 protein, mouse
  • Transcription Factors