Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation

Somineni, Hari K.; Venkateswaran, Suresh; Kilaru, Varun; Marigorta, Urko M.; Mo, Angela; Okou, David T.; Kellermayer, Richárd; Mondal, Kajari; Cobb, Dawayland; Walters, Thomas D.; Griffiths, Anne M.; Noe, Joshua D.; Crandall, Wallace; Rosh, Joel R.; Mack, David; Heyman, Melvin B.; Baker, Susan S.; Stephens, Michael C.; Baldassano, Robert N.; Markowitz, James; Dubinsky, Marla; Cho, Judy H.; Hyams, Jeffrey S.; Denson, Lee A.; Gibson, Greg; Cutler, David J.; Conneely, Karen N.; Smith, Alicia K.; Kugathasan, Subra

doi:10.1053/j.gastro.2019.01.270

Cited by 115 publications

(148 citation statements)

References 47 publications

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“…Different characteristics of DNA methylation, such as its relative stability, make this mark an ideal sensor of disease risk and progression. Indeed, several studies have been able to use DNA methylation as a marker of IBD in blood samples [31,35,36]. Both in blood and intestinal mucosa, a deeper mechanistic insight is necessary to better distinguish those methyl marks that are dependent on genetic susceptibility from those that are a consequence of environmental cues.…”

Section: Discussionmentioning

confidence: 99%

The DNA methylome of inflammatory bowel disease (IBD) reflects intrinsic and extrinsic factors in intestinal mucosal cells

et al. 2020

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Abnormal DNA methylation has been described in human inflammatory conditions of the gastrointestinal tract, such as inflammatory bowel disease (IBD). As other complex diseases, IBD results from the balance between genetic predisposition and environmental exposures. As such, DNA methylation may be the consequence (and potential effector) of both, genetic susceptibility variants and/or environmental signals such as cytokine exposure. We attempted to discern between these two non-excluding possibilities by performing a combined analysis of published DNA methylation data in intestinal mucosal cells of IBD and control samples. We identified abnormal DNA methylation at different levels: deviation from mean methylation signals at site and region levels, and differential variability. A fraction of such changes is associated with genetic polymorphisms linked to IBD susceptibility. In addition, by comparing with another intestinal inflammatory condition (i.e., coeliac disease) we propose that aberrant DNA methylation can also be the result of unspecific processes such as chronic inflammation. Our characterization suggests that IBD methylomes combine intrinsic and extrinsic responses in intestinal mucosal cells, and could point to knowledge-based biomarkers of IBD detection and progression.

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Section: Discussionmentioning

confidence: 99%

The DNA methylome of inflammatory bowel disease (IBD) reflects intrinsic and extrinsic factors in intestinal mucosal cells

et al. 2020

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“…The constancy of this dysfunctional phenotype might reflect changes at the epigenetic level, which ultimately hamper the resolution of the inflammatory events in the sinus of the affected mesenteric AT. In support of this proposition, recent DNA methylation studies in peripheral blood mononuclear cells (PBMCs) revealed that patients with CD have a distinct DNA methylome linked to the expression of differentially methylated genes associated with immune response and inflammation [19][20][21]. We hypothesized that hASCs from patients with CD are conditioned by a chronic inflammatory milieu, which may alter their DNA methylome and influence their antiinflammatory and regenerative capacity.…”

Section: Introductionmentioning

confidence: 94%

“…Donors were classified as those in relapse (active) or in remission (inactive) according to the CDAI score as well as biological and clinical parameters such as PCR and fecal calprotectin. Furthermore, endoscopic evaluation was performed in the majority of patients [20,21,50,51]. Healthy subjects and donors with inactive CD were recruited from ageand gender-matched subjects undergoing non-acute surgical interventions such as hernia or cholecystectomy, in a scheduled routine surgery.…”

Section: Study Populationmentioning

confidence: 99%

Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

et al. 2020

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Background: Crohn's disease (CD) is characterized by persistent inflammation and ulceration of the small or large bowel, and expansion of mesenteric adipose tissue, termed creeping fat (CF). We previously demonstrated that human adipose-derived stem cells (hASCs) from CF of patients with CD exhibit dysfunctional phenotypes, including a pro-inflammatory profile, high phagocytic capacity, and weak immunosuppressive properties. Importantly, these phenotypes persist in patients in remission and are found in all adipose depots explored including subcutaneous fat. We hypothesized that changes in hASCs are a consequence of epigenetic modifications. Methods: We applied epigenome-wide profiling with a methylation array (Illumina EPIC/850k array) and gene expression analysis to explore the impact of CD on the methylation signature of hASCs isolated from the subcutaneous fat of patients with CD and healthy controls (n = 7 and 5, respectively; cohort I). Differentially methylated positions (p value cutoff < 1 × 10 −4 and ten or more DMPs per gene) and regions (inclusion threshold 0.2, p value cutoff < 1 × 10 −2 and more than 2 DMRs per gene) were identified using dmpfinder and Bumphunter (minfi), respectively. Changes in the expression of differentially methylated genes in hASCs were validated in a second cohort (n = 10/10 inactive and active CD and 10 controls; including patients from cohort I) and also in peripheral blood mononuclear cells (PBMCs) of patients with active/inactive CD and of healthy controls (cohort III; n = 30 independent subjects). Results: We found a distinct DNA methylation landscape in hASCs from patients with CD, leading to changes in the expression of differentially methylated genes involved in immune response, metabolic, cell differentiation, and development processes. Notably, the expression of several of these genes in hASCs and PBMCs such as tumor necrosis factor alpha (TNFA) and PR domain zinc finger protein 16 (PRDM16) were not restored to normal (healthy) levels after disease remission. Conclusions: hASCs of patients with CD exhibit a unique DNA methylation and gene expression profile, but the expression of several genes are only partially restored in patients with inactive CD, both in hASCs and PBMCs. Understanding how CD shapes the functionality of hASCs is critical for investigating the complex pathophysiology of this disease, as well as for the success of cell-based therapies.

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“…One of the first studies on ulcerative colitis patients performed methylation analysis on mucosal biopsies and identified increased methylation of promoter regions 220 . More recently, a study on methylation pattern on blood samples from paediatric inflammatory bowel disease donors indicated that Crohn's disease‐associated patterns of DNA methylation observed are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression 221 . Comments on that study highlighted the positive points, especially the identification of a target gene RPS6KA2 (encoding the enzyme ribosomal protein S6 kinase alpha‐2), that has been shown in previous study to be significantly hypomethylated in inflammatory bowel disease across several independent paediatric and adult cohorts 222 .…”

Section: Introductionmentioning

confidence: 99%

Review article: impact of cigarette smoking on intestinal inflammation—direct and indirect mechanisms

Παπουτσοπουλου

Satsangi

Campbell

et al. 2020

Aliment Pharmacol Ther

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Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation

Cited by 115 publications

References 47 publications

The DNA methylome of inflammatory bowel disease (IBD) reflects intrinsic and extrinsic factors in intestinal mucosal cells

The DNA methylome of inflammatory bowel disease (IBD) reflects intrinsic and extrinsic factors in intestinal mucosal cells

Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

Review article: impact of cigarette smoking on intestinal inflammation—direct and indirect mechanisms

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