title: Distinct genomic and epigenomic features demarcate hypomethylated blocks in colon cancer.
abstract: BACKGROUND
  Large mega base-pair genomic regions show robust alterations in DNA methylation levels in multiple cancers. A vast majority of these regions are hypomethylated in cancers. These regions are generally enriched for CpG islands, Lamin Associated Domains and Large organized chromatin lysine modification domains, and are associated with stochastic variability in gene expression. Given the size and consistency of hypomethylated blocks (HMB) across cancer types, we hypothesized that the immediate causes of methylation instability are likely to be encoded in the genomic region near HMB boundaries, in terms of specific genomic or epigenomic signatures. However, a detailed characterization of the HMB boundaries has not been reported.
  
  
  METHODS
  Here, we focused on ~13 k HMBs, encompassing approximately half of the genome, identified in colon cancer. We modeled the genomic features of HMB boundaries by Random Forest to identify their salient features, in terms of transcription factor (TF) binding motifs. Additionally we analyzed various epigenomic marks, and chromatin structural features of HMB boundaries relative to the non-HMB genomic regions.
  
  
  RESULTS
  We found that the classical promoter epigenomic mark--H3K4me3, is highly enriched at HMB boundaries, as are CTCF bound sites. HMB boundaries harbor distinct combinations of TF motifs. Our Random Forest model based on TF motifs can accurately distinguish boundaries not only from regions inside and outside HMBs, but surprisingly, from active promoters as well. Interestingly, the distinguishing TFs and their interacting proteins are involved in chromatin modification. Finally, HMB boundaries significantly coincide with the boundaries of Topologically Associating Domains of the chromatin.
  
  
  CONCLUSIONS
  Our analyses suggest that the overall architecture of HMBs is guided by pre-existing chromatin architecture, and are associated with aberrant activity of promoter-like sequences at the boundary.
authors: Department of Computer Science, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA.
authors: Mahfuza
authors: M
authors: Sharmin
authors: Department of Computer Science, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA. hcorrada@umiacs.umd.edu.
authors: Héctor Corrada
authors: HC
authors: Bravo
authors: Department of Cell and Molecular Biology, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA. sridhar@umiacs.umd.edu.
authors: Sridhar
authors: S
authors: Hannenhalli
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D015894:Genome, Human; D006657:Histones / Q000235:genetics; D006801:Humans; D011401:Promoter Regions, Genetic
chemical_list: D002843:Chromatin; D006657:Histones