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Abstract Number: 755

Genome-Wide DNA Methylation Pattern in Systemic Sclerosis Microvascular Endothelial Cells:  Identification of Epigenetically Affected Key Genes and Pathways

Shadia Nada1, Ibtissam Gad2, Ali Alqahtani3, Ahmad Assaly2, Sadik Khuder4, Yongqing Wang5, Bashar Kahaleh1 and Nezam Altorok1, 1Medicine/Rheumatology, University of Toledo, Toledo, OH, 2University of Toledo, Toledo, OH, 3Internal Medicine, University of Toledo, Toledo, OH, 4Department of Medicine, University of Toledo, Toledo, OH, 5Medicine, University of Toledo, Toledo, OH

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: DNA Methylation, endothelial cells, Epigenetics, systemic sclerosis and vasculogenesis

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Session Information

Date: Sunday, November 5, 2017

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: The etiology of systemic sclerosis (SSc) is not clear, but there is evidence suggesting a critical role for epigenetic alterations in disease pathogenesis and clinical expression. We sought in this study to characterize the genome wide DNA methylation signature in SSc Microvascular Endothelial Cells (MVECs).

Methods: We performed a genome-wide DNA methylation study in MVECs derived from 7 diffuse cutaneous SSc (dSSc) patients compared to 7 age, sex, and ethnicity-matched healthy controls. Cytosine methylation was quantified across the genome. We divided samples from patients and controls in two groups of matched SSc subjects and controls. Differentially methylated CpG sites between patients and controls were identified by fold difference in methylation level ≥ 1.2, and false discovery rate (FDR) adjusted P value <0.01. Moreover, quantitative real-time RT-PCR was performed to assess the correlation between DNA methylation and gene expression levels in selected genes.

Results: We identified 71,353 differentially methylated CpG sites in SSc-MVECs using Infinium MethylationEPIC microarray in the first group (0.081% of representative probes), and 33,170 CpG sites in the second group using HumanMethylation 450 microarray (0.073% of representative probes) in dcSSc-MVEC. Among the two groups of subjects, we identified differential methylation of 2,455 CpG sites, representing 1,301 genes. Most of the differentially methylated CpG sites were hypermethylated (1,625 CpG), corresponding to 910 genes. There were 830 hypomethylated CpG sites, representing 485 genes. Common Hypermethylated genes in SSc MVECs include NOS1, which encodes for nitric oxide synthase -1, DNMT3A, DNMT3B, HDAC4 and ANGPT2. We also identified hypomethylation of IL17RA, CTNNA3, ICAM2 and SDK1in SSc MVECs. Furthermore, we demonstrate significant inverse correlation between DNA methylation status and gene expression in the majority of genes evaluated.

Gene ontology analysis of hypermethylated genes demonstrated enrichment of genes involved in homophilic cell adhesion via plasma membrane adhesion molecules (P= 2.10E-07) and angiogenesis (P= 0.0006). Pathway analysis of hypomethylated genes includes genes involved in Wnt signaling pathway (P= 0.001), vascular smooth muscle contraction (P= 0.014) and adherens junctions (P 0.013).

Conclusion : Our data suggest the presence of significant genome-wide DNA methylation aberrancies in SSc-MVEC, and identify novel affected genes and pathways in SSc MVECs.


Disclosure: S. Nada, None; I. Gad, None; A. Alqahtani, None; A. Assaly, None; S. Khuder, None; Y. Wang, None; B. Kahaleh, None; N. Altorok, None.

To cite this abstract in AMA style:

Nada S, Gad I, Alqahtani A, Assaly A, Khuder S, Wang Y, Kahaleh B, Altorok N. Genome-Wide DNA Methylation Pattern in Systemic Sclerosis Microvascular Endothelial Cells:  Identification of Epigenetically Affected Key Genes and Pathways [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/genome-wide-dna-methylation-pattern-in-systemic-sclerosis-microvascular-endothelial-cells-identification-of-epigenetically-affected-key-genes-and-pathways/. Accessed January 27, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-pattern-in-systemic-sclerosis-microvascular-endothelial-cells-identification-of-epigenetically-affected-key-genes-and-pathways/

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