title: Integrative ChIP-seq/microarray analysis identifies a CTNNB1 target signature enriched in intestinal stem cells and colon cancer.
abstract: BACKGROUND
  Deregulation of canonical Wnt/CTNNB1 (beta-catenin) pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 are highly frequent in colon cancer and cause aberrant stabilization of CTNNB1, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of CTNNB1 by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of CTNNB1 in colon cancer cells.
  
  
  RESULTS
  We observed 3629 CTNNB1 binding peaks across the genome and a significant correlation between CTNNB1 binding and knockdown-induced gene expression change. Our integrative analysis led to the discovery of a direct Wnt target signature composed of 162 genes. Gene ontology analysis of this signature revealed a significant enrichment of Wnt pathway genes, suggesting multiple feedback regulations of the pathway. We provide evidence that this gene signature partially overlaps with the Lgr5+ intestinal stem cell signature, and is significantly enriched in normal intestinal stem cells as well as in clinical colorectal cancer samples. Interestingly, while the expression of the CTNNB1 target gene set does not correlate with survival, elevated expression of negative feedback regulators within the signature predicts better prognosis.
  
  
  CONCLUSIONS
  Our data provide a genome-wide view of chromatin occupancy and gene regulation of Wnt/CTNNB1 signaling in colon cancer cells.
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, California, United States of America.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, California, United States of America; Department of Computer Science, University of California Irvine, Irvine, California, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Biesinger
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, California, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Salmans
authors.affiliation: Rosetta Inpharmatics, LLC, Merck & Co Inc., Seattle, Washington, United States of America.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Roberts
authors.affiliation: Rosetta Inpharmatics, LLC, Merck & Co Inc., Seattle, Washington, United States of America.
authors.forename: William T
authors.initials: WT
authors.lastname: Arthur
authors.affiliation: Rosetta Inpharmatics, LLC, Merck & Co Inc., Seattle, Washington, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Cleary
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, California, United States of America.
authors.forename: Bogi
authors.initials: B
authors.lastname: Andersen
authors.affiliation: Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, California, United States of America; Department of Computer Science, University of California Irvine, Irvine, California, United States of America.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, California, United States of America; Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, California, United States of America.
authors.forename: Xing
authors.initials: X
authors.lastname: Dai
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics*; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D006801:Humans; D007422:Intestines / Q000473:pathology*; D053208:Kaplan-Meier Estimate; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D012984:Software; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D002843:Chromatin; D051176:beta Catenin