Dataset Information

DNA Methylation-Governed Gene Expression in Autoimmune Arthritis.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease hallmarked by progressive and irreversible joint destruction. RA pathogenesis is a T cell-regulated and B cell-mediated process in which activated lymphocyte-produced chemokines and cytokines promote leukocyte infiltration that ultimately leads to destruction of the joints. There is an obvious need to discover new drugs for RA treatment that have different biological targets or modes of action than the currently employed therapeutics. Environmental factors such as cigarette smoke, certain diet components, and oral pathogens can significantly affect gene regulation via epigenetic factors. Epigenetics opened a new field for pharmacology, and DNA methylation and histone modification-implicated factors are feasible targets for RA therapy. Exploring RA pathogenesis involved epigenetic factors and mechanisms is crucial for developing more efficient RA therapies. Here we review epigenetic alterations associated with RA pathogenesis including DNA methylation and interacting factors. Additionally, we will summarize the literature revealing the involved molecular structures and interactions. Finally, potential epigenetic factor-based therapies will be discussed that may help in better management of RA in the future.

SUBMITTER: Brandt B

PROVIDER: S-EPMC6888626 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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DNA Methylation-Governed Gene Expression in Autoimmune Arthritis.

Brandt Barbara B Rashidiani Shima S Bán Ágnes Á Rauch Tibor A TA

International journal of molecular sciences 20191112 22

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease hallmarked by progressive and irreversible joint destruction. RA pathogenesis is a T cell-regulated and B cell-mediated process in which activated lymphocyte-produced chemokines and cytokines promote leukocyte infiltration that ultimately leads to destruction of the joints. There is an obvious need to discover new drugs for RA treatment that have different biological targets or modes of action than the currently employed ther ...[more]

PMID: 31718084

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Project description:BackgroundThe integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event.ResultsFour independent latent factors (9, 19, 21-only in women-and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination.ConclusionsUnsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.

Project description:Our previously published data link P-selectin-reactive chondroitin sulfate structures on the surface of breast cancer cells to metastatic behavior of cells. We have shown that a particular sulfation pattern mediated by the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) correlates with P-selectin binding and aggressiveness of human breast cancer cell lines. The present study was performed to evaluate the prognostic value of CHST11 expression and determine whether aberrant DNA methylation controls CHST11 expression in breast cancer. Publicly available datasets were used to examine the association of CHST11 expression to aggressiveness and progression of breast cancer. Methylation status was analyzed using bisulfite genomic sequencing. 5-aza-2'-deoxycytidine (5AzadC) was used for DNA demethylation. Reduced representation bisulfite sequencing was performed in the CpG island of CHST11 with a minimum coverage of 10. Quantitative real-time RT-PCR was employed to confirm the expression profile of CHST11 in breast cancer cell lines. Flow cytometry was also used to confirm the expression of the CHST11 product, chondroitin sulfate A (CS-A). The expression of CHST11 was significantly higher in basal-like and Her2-amplified cell lines compared to luminal cell lines. CHST11 was also highly expressed in cancer tissues compared to normal tissues and the expression levels were significantly associated with tumor progression. We observed very low levels of DNA methylation in a CpG island of CHST11 in basal-like cells but very high levels in the same region in luminal cells. Treatment of MCF7 cells, a luminal cell line with very low expression of CHST11, with 5AzadC increased the expression of CHST11 and its immediate product, CS-A, in a dose-dependent manner. These results suggest that CHST11 may play a direct role in progression of breast cancer and that its expression is controlled by DNA methylation. Therefore, in addition to CHST11 mRNA levels, the methylation status of this gene also has potential as a prognostic biomarker.

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Dataset Information

DNA Methylation-Governed Gene Expression in Autoimmune Arthritis.

Publications

DNA Methylation-Governed Gene Expression in Autoimmune Arthritis.

Similar Datasets

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