title: Hypomethylation coordinates antagonistically with hypermethylation in cancer development: a case study of leukemia.
abstract: Methylation changes are frequent in cancers, but understanding how hyper- and hypomethylated region changes coordinate, associate with genomic features, and affect gene expression is needed to better understand their biological significance. The functional significance of hypermethylation is well studied, but that of hypomethylation remains limited. Here, with paired expression and methylation samples gathered from a patient/control cohort, we attempt to better characterize the gene expression and methylation changes that take place in cancer from B cell chronic lymphocyte leukemia (B-CLL) samples.
  
  
  
  Across the dataset, we found that consistent differentially hypomethylated regions (C-DMRs) across samples were relatively few compared to the many poorly consistent hypo- and highly conserved hyper-DMRs. However, genes in the hypo-C-DMRs tended to be associated with functions antagonistic to those in the hyper-C-DMRs, like differentiation, cell-cycle regulation and proliferation, suggesting coordinated regulation of methylation changes. Hypo-C-DMRs in B-CLL were found enriched in key signaling pathways like B cell receptor and p53 pathways and genes/motifs essential for B lymphopoiesis. Hypo-C-DMRs tended to be proximal to genes with elevated expression in contrast to the transcription silencing-mechanism imposed by hypermethylation. Hypo-C-DMRs tended to be enriched in the regions of activating H4K4me1/2/3, H3K79me2, and H3K27ac histone modifications. In comparison, the polycomb repressive complex 2 (PRC2) signature, marked by EZH2, SUZ12, CTCF binding-sites, repressive H3K27me3 marks, and "repressed/poised promoter" states were associated with hyper-C-DMRs. Most hypo-C-DMRs were found in introns (36 %), 3' untranslated regions (29 %), and intergenic regions (24 %). Many of these genic regions also overlapped with enhancers. The methylation of CpGs from 3'UTR exons was found to have weak but positive correlation with gene expression. In contrast, methylation in the 5'UTR was negatively correlated with expression. To better characterize the overlap between methylation and expression changes, we identified correlation modules that associate with "apoptosis" and "leukocyte activation".
  
  
  
  Despite clinical heterogeneity in disease presentation, a number of methylation changes, both hypo and hyper, appear to be common in B-CLL. Hypomethylation appears to play an active, targeted, and complementary role in cancer progression, and it interplays with hypermethylation in a coordinated fashion in the cancer process.
authors.affiliation: Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA.|Informatics Institute, University of Missouri, Columbia, MO, 65211, USA.
authors.forename: Garima
authors.initials: G
authors.lastname: Kushwaha
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, 23225, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Dozmorov
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Department of Applied Economics & Statistics, University of Delaware, Newark, DE, 19716, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA. hshi@gru.edu.|Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, 30912, USA. hshi@gru.edu.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA. xudong@missouri.edu.|Informatics Institute, University of Missouri, Columbia, MO, 65211, USA. xudong@missouri.edu.|Department of Computer Science, University of Missouri, Columbia, MO, 65211, USA. xudong@missouri.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D063990:Gene Ontology; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data; D006657:Histones / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones
keywords: 3′UTR; CLL; Cancer; DNA methylation; Enhancer; Epigenetic regulation; Hypomethylation; Signaling pathway