A hidden Markov model for analyzing ChIP-chip experiments on genome tiling arrays and its application to p53 binding sequences.
BACKGROUND
Transcription factors (TFs) regulate gene expression by recognizing and binding to specific regulatory regions on the genome, which in higher eukaryotes can occur far away from the regulated genes. Recently, Affymetrix developed the high-density oligonucleotide arrays that tile all the non-repetitive sequences of the human genome at 35 bp resolution. This new array platform allows for the unbiased mapping of in vivo TF binding sequences (TFBSs) using Chromatin ImmunoPrecipitation followed by microarray experiments (ChIP-chip). The massive dataset generated from these experiments pose great challenges for data analysis.


RESULTS
We developed a fast, scalable and sensitive method to extract TFBSs from ChIP-chip experiments on genome tiling arrays. Our method takes advantage of tiling array data from many experiments to normalize and model the behavior of each individual probe, and identifies TFBSs using a hidden Markov model (HMM). When applied to the data of p53 ChIP-chip experiments from an earlier study, our method discovered many new high confidence p53 targets including all the regions verified by quantitative PCR. Using a de novo motif finding algorithm MDscan, we also recovered the p53 motif from our HMM identified p53 target regions. Furthermore, we found substantial p53 motif enrichment in these regions comparing with both genomic background and the TFBSs identified earlier. Several of the newly identified p53 TFBSs are in the promoter region of known genes or associated with previously characterized p53-responsive genes.


BACKGROUND
Available at the following URL http://genome.dfci.harvard.edu/~xsliu/HMMTiling/index.html.
Li
Wei
W
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health Boston, MA 02115, USA.
Meyer
Clifford A
CA
Liu
X Shirley
XS
D020816:Amino Acid Motifs; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods*; D018899:CpG Islands; D016158:Genes, p53; D016678:Genome; D015894:Genome, Human; D006801:Humans; D008390:Markov Chains; D015233:Models, Statistical; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009841:Oligonucleotides; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53