Hypomethylation coordinates antagonistically with hypermethylation in cancer development

A case study of leukemia

Garima Kushwaha, Mikhail Dozmorov, Jonathan D. Wren, Jing Qiu, Huidong Shi, Dong Xu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: 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. Results: 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". Conclusions: 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.

Original languageEnglish (US)
Article number18
JournalHuman Genomics
Volume10
DOIs
StatePublished - Jan 1 2016

Fingerprint

Methylation
Leukemia
Neoplasms
B-Cell Chronic Lymphocytic Leukemia
3' Untranslated Regions
Lymphocytes
Gene Expression
Polycomb Repressive Complex 2
Histone Code
Lymphopoiesis
Intergenic DNA
5' Untranslated Regions
p53 Genes
Introns
Genes
Exons
Cell Cycle
Leukocytes
B-Lymphocytes
Binding Sites

Keywords

  • 3′ UTR
  • CLL
  • Cancer
  • DNA methylation
  • Enhancer
  • Epigenetic regulation
  • Hypomethylation
  • Signaling pathway

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery

Cite this

Hypomethylation coordinates antagonistically with hypermethylation in cancer development : A case study of leukemia. / Kushwaha, Garima; Dozmorov, Mikhail; Wren, Jonathan D.; Qiu, Jing; Shi, Huidong; Xu, Dong.

In: Human Genomics, Vol. 10, 18, 01.01.2016.

Research output: Contribution to journalArticle

Kushwaha, Garima ; Dozmorov, Mikhail ; Wren, Jonathan D. ; Qiu, Jing ; Shi, Huidong ; Xu, Dong. / Hypomethylation coordinates antagonistically with hypermethylation in cancer development : A case study of leukemia. In: Human Genomics. 2016 ; Vol. 10.
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keywords = "3′ UTR, CLL, Cancer, DNA methylation, Enhancer, Epigenetic regulation, Hypomethylation, Signaling pathway",
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AU - Kushwaha, Garima

AU - Dozmorov, Mikhail

AU - Wren, Jonathan D.

AU - Qiu, Jing

AU - Shi, Huidong

AU - Xu, Dong

PY - 2016/1/1

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N2 - Background: 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. Results: 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". Conclusions: 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.

AB - Background: 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. Results: 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". Conclusions: 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.

KW - 3′ UTR

KW - CLL

KW - Cancer

KW - DNA methylation

KW - Enhancer

KW - Epigenetic regulation

KW - Hypomethylation

KW - Signaling pathway

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