S Mahurkar1, C Polytarchou2, D Iliopoulos2, C Pothoulakis3, E A Mayer1, L Chang1. 1. Oppenheimer Center for Neurobiology of Stress at UCLA, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 2. Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 3. Department of Medicine, Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Abstract
BACKGROUND: Irritable bowel syndrome (IBS) is a stress-sensitive disorder. Environmental factors including stress can trigger epigenetic changes, which have not been well-studied in IBS. We performed a pilot study investigating genome-wide DNA methylation of IBS patients and healthy controls (HCs) to identify potential epigenetic markers and associated pathways. Additionally, we investigated relationships of epigenetic changes in selected genes with clinical traits. METHODS: Twenty-seven IBS patients (59% women; 10 IBS-diarrhea, 8 IBS-constipation, 9 IBS-mixed) and 23 age- and sex-matched HCs were examined. DNA methylation from peripheral blood mononuclear cells (PBMCs) was measured using HM450 BeadChip, and representative methylation differences were confirmed by bisulphite sequencing. Gene expression was measured using quantitative PCR. Gastrointestinal (GI) and non-GI symptoms were measured using validated questionnaires. Associations were tested using non-parametric methods. KEY RESULTS: Genome-wide DNA methylation profiling of IBS patients compared with HCs identified 133 differentially methylated positions (DMPs) (mean difference ≥10%; p < 0.05). These genes were associated with gene ontology terms including glutathione metabolism related to oxidative stress and neuropeptide hormone activity. Validation by sequencing confirmed differential methylation of subcommissural organ (SCO)-Spondin (SSPO), glutathione-S-transferases mu 5 (GSTM5), and tubulin polymerization promoting protein genes. Methylation of two promoter CpGs in GSTM5 was associated with epigenetic silencing. Epigenetic changes in SSPO gene were positively correlated with hospital anxiety and depression scores in IBS patients (r > 0.4 and false discovery rate <0.05). CONCLUSIONS & INFERENCES: This study is the first to comprehensively explore the methylome of IBS patients. We identified DMPs in novel candidate genes which could provide new insights into disease mechanisms; however, these preliminary findings warrant confirmation in larger, independent studies.
BACKGROUND:Irritable bowel syndrome (IBS) is a stress-sensitive disorder. Environmental factors including stress can trigger epigenetic changes, which have not been well-studied in IBS. We performed a pilot study investigating genome-wide DNA methylation of IBSpatients and healthy controls (HCs) to identify potential epigenetic markers and associated pathways. Additionally, we investigated relationships of epigenetic changes in selected genes with clinical traits. METHODS: Twenty-seven IBSpatients (59% women; 10 IBS-diarrhea, 8 IBS-constipation, 9 IBS-mixed) and 23 age- and sex-matched HCs were examined. DNA methylation from peripheral blood mononuclear cells (PBMCs) was measured using HM450 BeadChip, and representative methylation differences were confirmed by bisulphite sequencing. Gene expression was measured using quantitative PCR. Gastrointestinal (GI) and non-GI symptoms were measured using validated questionnaires. Associations were tested using non-parametric methods. KEY RESULTS: Genome-wide DNA methylation profiling of IBSpatients compared with HCs identified 133 differentially methylated positions (DMPs) (mean difference ≥10%; p < 0.05). These genes were associated with gene ontology terms including glutathione metabolism related to oxidative stress and neuropeptide hormone activity. Validation by sequencing confirmed differential methylation of subcommissural organ (SCO)-Spondin (SSPO), glutathione-S-transferases mu 5 (GSTM5), and tubulin polymerization promoting protein genes. Methylation of two promoter CpGs in GSTM5 was associated with epigenetic silencing. Epigenetic changes in SSPO gene were positively correlated with hospital anxiety and depression scores in IBSpatients (r > 0.4 and false discovery rate <0.05). CONCLUSIONS & INFERENCES: This study is the first to comprehensively explore the methylome of IBSpatients. We identified DMPs in novel candidate genes which could provide new insights into disease mechanisms; however, these preliminary findings warrant confirmation in larger, independent studies.
Authors: Michael Camilleri; Paula Carlson; Andres Acosta; Irene Busciglio; Asha A Nair; Simon J Gibbons; Gianrico Farrugia; Eric W Klee Journal: Am J Physiol Gastrointest Liver Physiol Date: 2014-04-24 Impact factor: 4.052
Authors: S Gobron; I Creveaux; R Meiniel; R Didier; A Herbet; M Bamdad; F El Bitar; B Dastugue; A Meiniel Journal: Glia Date: 2000-11 Impact factor: 7.452
Authors: Hyang-Min Byun; Kimberly D Siegmund; Fei Pan; Daniel J Weisenberger; Gary Kanel; Peter W Laird; Allen S Yang Journal: Hum Mol Genet Date: 2009-09-23 Impact factor: 6.150
Authors: Lesha Pretorius; Anton du Preez Van Staden; Johannes J Van der Merwe; Natasha Henning; Carine Smith Journal: Inflammopharmacology Date: 2022-01-13 Impact factor: 4.473
Authors: John Paul Spence; Dongbing Lai; Jill L Reiter; Sha Cao; Richard L Bell; Kent E Williams; Tiebing Liang Journal: Alcohol Date: 2020-08-14 Impact factor: 2.405
Authors: Malav S Trivedi; Elisa Oltra; Leonor Sarria; Natasha Rose; Vladimir Beljanski; Mary Ann Fletcher; Nancy G Klimas; Lubov Nathanson Journal: PLoS One Date: 2018-07-23 Impact factor: 3.240