DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis

Edel McDermott; Elizabeth J. Ryan; Miriam Tosetto; David Gibson; Joe Burrage; Denise Keegan; Kathryn Byrne; Eimear Crowe; Gillian Sexton; Kevin Malone; R. Alan Harris; Richard Kellermayer; Jonathan Mill; Garret Cullen; Glen A. Doherty; Hugh Mulcahy; Therese M. Murphy

doi:10.1093/ecco-jcc/jjv176

DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis

Edel McDermott, Elizabeth J. Ryan, Miriam Tosetto, David Gibson, Joe Burrage, Denise Keegan, Kathryn Byrne, Eimear Crowe, Gillian Sexton, Kevin Malone, R. Alan Harris, Richard Kellermayer, Jonathan Mill, Garret Cullen, Glen A. Doherty, Hugh Mulcahy, Therese M. Murphy

Research output: Contribution to journal › Article › peer-review

109 Citations (Scopus)

Abstract

Background and Aims: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity. Methods: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. Results: A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. Conclusions: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.

Original language	English
Pages (from-to)	77-86
Number of pages	10
Journal	Journal of Crohn's and Colitis
Volume	10
Issue number	1
DOIs	https://doi.org/10.1093/ecco-jcc/jjv176
Publication status	Published - 1 Jan 2016
Externally published	Yes

Keywords

DNA methylation
Epigenetics
inflammatory bowel disease

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10.1093/ecco-jcc/jjv176

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McDermott, E., Ryan, E. J., Tosetto, M., Gibson, D., Burrage, J., Keegan, D., Byrne, K., Crowe, E., Sexton, G., Malone, K., Harris, R. A., Kellermayer, R., Mill, J., Cullen, G., Doherty, G. A., Mulcahy, H., & Murphy, T. M. (2016). DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis. Journal of Crohn's and Colitis, 10(1), 77-86. https://doi.org/10.1093/ecco-jcc/jjv176

@article{e4801f9ad829467ca7b4cd777a61ab57,

title = "DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis",

abstract = "Background and Aims: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity. Methods: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. Results: A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. Conclusions: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.",

keywords = "DNA methylation, Epigenetics, inflammatory bowel disease",

author = "Edel McDermott and Ryan, {Elizabeth J.} and Miriam Tosetto and David Gibson and Joe Burrage and Denise Keegan and Kathryn Byrne and Eimear Crowe and Gillian Sexton and Kevin Malone and Harris, {R. Alan} and Richard Kellermayer and Jonathan Mill and Garret Cullen and Doherty, {Glen A.} and Hugh Mulcahy and Murphy, {Therese M.}",

note = "Funding Information: This research was supported by a grant from AbbVie (no. 10118). EMcD was the recipient of the Boston Scientific Newman Fellowship awarded by the UCD Foundation. RK was supported by Gutsy Kids Fund, including philanthropic donation from the Karen and Brock Wagner family, the Houston Men of Distinction and the National Institutes of Health (P30 DK56338).",

year = "2016",

month = jan,

day = "1",

doi = "10.1093/ecco-jcc/jjv176",

language = "English",

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journal = "Journal of Crohn's and Colitis",

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McDermott, E, Ryan, EJ, Tosetto, M, Gibson, D, Burrage, J, Keegan, D, Byrne, K, Crowe, E, Sexton, G, Malone, K, Harris, RA, Kellermayer, R, Mill, J, Cullen, G, Doherty, GA, Mulcahy, H & Murphy, TM 2016, 'DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis', Journal of Crohn's and Colitis, vol. 10, no. 1, pp. 77-86. https://doi.org/10.1093/ecco-jcc/jjv176

TY - JOUR

T1 - DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis

AU - McDermott, Edel

AU - Ryan, Elizabeth J.

AU - Tosetto, Miriam

AU - Gibson, David

AU - Burrage, Joe

AU - Keegan, Denise

AU - Byrne, Kathryn

AU - Crowe, Eimear

AU - Sexton, Gillian

AU - Malone, Kevin

AU - Harris, R. Alan

AU - Kellermayer, Richard

AU - Mill, Jonathan

AU - Cullen, Garret

AU - Doherty, Glen A.

AU - Mulcahy, Hugh

AU - Murphy, Therese M.

N1 - Funding Information: This research was supported by a grant from AbbVie (no. 10118). EMcD was the recipient of the Boston Scientific Newman Fellowship awarded by the UCD Foundation. RK was supported by Gutsy Kids Fund, including philanthropic donation from the Karen and Brock Wagner family, the Houston Men of Distinction and the National Institutes of Health (P30 DK56338).

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background and Aims: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity. Methods: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. Results: A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. Conclusions: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.

AB - Background and Aims: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity. Methods: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. Results: A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. Conclusions: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.

KW - DNA methylation

KW - Epigenetics

KW - inflammatory bowel disease

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U2 - 10.1093/ecco-jcc/jjv176

DO - 10.1093/ecco-jcc/jjv176

M3 - Article

C2 - 26419460

AN - SCOPUS:84963738636

SN - 1873-9946

VL - 10

SP - 77

EP - 86

JO - Journal of Crohn's and Colitis

JF - Journal of Crohn's and Colitis

IS - 1

ER -

DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis

Abstract

Keywords

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