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Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma.

Aine M, Sjödahl G, Eriksson P, Veerla S, Lindgren D, Ringnér M, Höglund M - Genome Med (2015)

Bottom Line: We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes.Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC.UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

ABSTRACT

Background: Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors.

Methods: We perform genome-wide DNA methylation profiling of 98 gene-expression subtyped tumors to identify between-tumor differentially methylated regions (DMRs). We integrate multi-level publically available genomic data generated by the ENCODE consortium to characterize the regulatory potential of UC DMRs.

Results: We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes. We characterize three distinct patterns of differential methylation and use ENCODE data to show that tumor subgroup-defining DMRs display differential chromatin state, and regulatory factor binding preferences. Finally, we characterize an epigenetic switch involving the HOXA-genes with associations to tumor differentiation states and patient prognosis.

Conclusions: Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC. UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences. Epigenetic inactivation of HOX-genes correlates with tumor differentiation states and may present an actionable epigenetic alteration in UC.

No MeSH data available.


Related in: MedlinePlus

Schematic summary of genomic associations to UC DMR methylation patterns. (A) Mean tumor subgroup methylation levels with respect to DMR methylation patterns. Methylation levels are indicated in blue (low) to red (high). (B) Pattern 1 to 3 DMRs display differential binding of regulatory factors in ENCODE cell lines. (C) A model of modes of RF binding at pattern 2 and pattern 3 DMRs, indicating differential regulatory function or modular organization underlying differential methylation. (D) Mean pattern 1 to 3 methylation levels in tumors belonging to the different HOXA methylation groups. (E) Lund gene expression subtype distribution across the HOXA methylation groups.
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Fig8: Schematic summary of genomic associations to UC DMR methylation patterns. (A) Mean tumor subgroup methylation levels with respect to DMR methylation patterns. Methylation levels are indicated in blue (low) to red (high). (B) Pattern 1 to 3 DMRs display differential binding of regulatory factors in ENCODE cell lines. (C) A model of modes of RF binding at pattern 2 and pattern 3 DMRs, indicating differential regulatory function or modular organization underlying differential methylation. (D) Mean pattern 1 to 3 methylation levels in tumors belonging to the different HOXA methylation groups. (E) Lund gene expression subtype distribution across the HOXA methylation groups.

Mentions: Previous studies into epigenetic changes in UC have mainly been focused on characterizing differential methylation [11,16,42-44]. However, the functional genomic context of differential methylation remains less well studied. We used multi-level genomic data generated through the ENCODE consortium to characterize the regulatory potential of UC DMRs and show that the identified regions exhibit biologically coherent chromatin state and RF-binding preferences in ENCODE cell-lines. We found that subgroup-defining DMRs exhibit three distinct patterns of methylation across tumors (summarized in Figure 8A). Pattern 1 DMRs are located in low CpG-density, repeat-rich, subtelomeric regions of the genome and are depleted of functional chromatin states and RF-binding across ENCODE cell lines. Methylation of pattern 1 DMRs is inversely correlated with pathological grade and may represent stochastic demethylation of heterochromatic DNA through a loss of a maintenance-like process, or may be a product of the formation of partially methylated domains (PMDs) [45] in a subset of tumors. The implications of subtelomeric and repetitive sequence demethylation for genome stability are not well understood but may contribute to UC pathogenesis and disease progression.Figure 8


Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma.

Aine M, Sjödahl G, Eriksson P, Veerla S, Lindgren D, Ringnér M, Höglund M - Genome Med (2015)

Schematic summary of genomic associations to UC DMR methylation patterns. (A) Mean tumor subgroup methylation levels with respect to DMR methylation patterns. Methylation levels are indicated in blue (low) to red (high). (B) Pattern 1 to 3 DMRs display differential binding of regulatory factors in ENCODE cell lines. (C) A model of modes of RF binding at pattern 2 and pattern 3 DMRs, indicating differential regulatory function or modular organization underlying differential methylation. (D) Mean pattern 1 to 3 methylation levels in tumors belonging to the different HOXA methylation groups. (E) Lund gene expression subtype distribution across the HOXA methylation groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4373102&req=5

Fig8: Schematic summary of genomic associations to UC DMR methylation patterns. (A) Mean tumor subgroup methylation levels with respect to DMR methylation patterns. Methylation levels are indicated in blue (low) to red (high). (B) Pattern 1 to 3 DMRs display differential binding of regulatory factors in ENCODE cell lines. (C) A model of modes of RF binding at pattern 2 and pattern 3 DMRs, indicating differential regulatory function or modular organization underlying differential methylation. (D) Mean pattern 1 to 3 methylation levels in tumors belonging to the different HOXA methylation groups. (E) Lund gene expression subtype distribution across the HOXA methylation groups.
Mentions: Previous studies into epigenetic changes in UC have mainly been focused on characterizing differential methylation [11,16,42-44]. However, the functional genomic context of differential methylation remains less well studied. We used multi-level genomic data generated through the ENCODE consortium to characterize the regulatory potential of UC DMRs and show that the identified regions exhibit biologically coherent chromatin state and RF-binding preferences in ENCODE cell-lines. We found that subgroup-defining DMRs exhibit three distinct patterns of methylation across tumors (summarized in Figure 8A). Pattern 1 DMRs are located in low CpG-density, repeat-rich, subtelomeric regions of the genome and are depleted of functional chromatin states and RF-binding across ENCODE cell lines. Methylation of pattern 1 DMRs is inversely correlated with pathological grade and may represent stochastic demethylation of heterochromatic DNA through a loss of a maintenance-like process, or may be a product of the formation of partially methylated domains (PMDs) [45] in a subset of tumors. The implications of subtelomeric and repetitive sequence demethylation for genome stability are not well understood but may contribute to UC pathogenesis and disease progression.Figure 8

Bottom Line: We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes.Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC.UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

ABSTRACT

Background: Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors.

Methods: We perform genome-wide DNA methylation profiling of 98 gene-expression subtyped tumors to identify between-tumor differentially methylated regions (DMRs). We integrate multi-level publically available genomic data generated by the ENCODE consortium to characterize the regulatory potential of UC DMRs.

Results: We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes. We characterize three distinct patterns of differential methylation and use ENCODE data to show that tumor subgroup-defining DMRs display differential chromatin state, and regulatory factor binding preferences. Finally, we characterize an epigenetic switch involving the HOXA-genes with associations to tumor differentiation states and patient prognosis.

Conclusions: Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC. UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences. Epigenetic inactivation of HOX-genes correlates with tumor differentiation states and may present an actionable epigenetic alteration in UC.

No MeSH data available.


Related in: MedlinePlus