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Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis

BACKGROUND: The currently known risk loci could explain a small proportion of the heritability of ankylosing spondylitis (AS). Epigenetics might account for the missing heritability. We aimed to seek more novel AS-associated DNA methylation alterations and delineate the regulatory effect of DNA meth...

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Autores principales: Xiao, Min, Zheng, Xuqi, Li, Xiaomin, Wu, Xinyu, Huang, Yefei, Wei, Qiujing, Cao, Shuangyan, Gu, Jieruo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728943/
https://www.ncbi.nlm.nih.gov/pubmed/34986893
http://dx.doi.org/10.1186/s13075-021-02697-3
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author Xiao, Min
Zheng, Xuqi
Li, Xiaomin
Wu, Xinyu
Huang, Yefei
Wei, Qiujing
Cao, Shuangyan
Gu, Jieruo
author_facet Xiao, Min
Zheng, Xuqi
Li, Xiaomin
Wu, Xinyu
Huang, Yefei
Wei, Qiujing
Cao, Shuangyan
Gu, Jieruo
author_sort Xiao, Min
collection PubMed
description BACKGROUND: The currently known risk loci could explain a small proportion of the heritability of ankylosing spondylitis (AS). Epigenetics might account for the missing heritability. We aimed to seek more novel AS-associated DNA methylation alterations and delineate the regulatory effect of DNA methylation and gene expression with integrated analysis of methylome and transcriptome. METHODS: Epigenome-wide DNA methylation and mRNA expression were profiled in peripheral blood mononuclear cells (PBMCs) from 45 individuals (AS: health controls (HCs) = 30:15) with high-throughput array. The methylome was validated in an independent cohort (AS: HCs = 12:12). Pearson correlation analysis and causal inference tests (CIT) were conducted to determine potentially causative regulatory effects of methylation on mRNA expression. RESULTS: A total of 4794 differentially methylated positions (DMPs) were identified associated with AS, 2526 DMPs of which were validated in an independent cohort. Both cohorts highlighted T cell receptor (TCR) signaling and Th17 differentiation pathways. Besides, AS patients manifested increased DNA methylation variability. The methylation levels of 158 DMPs were correlated with the mRNA expression levels of 112 genes, which formed interconnected network concentrated on Th17 cell differentiation and TCR signaling pathway (LCK, FYN, CD3G, TCF7, ZAP70, CXCL12, and PLCG1). We also identified several cis-acting DNA methylation and gene expression changes associated with AS risk, which might regulate the cellular mechanisms underlying AS. CONCLUSIONS: Our studies outlined the landscapes of epi-signatures of AS and several methylation-gene expression-AS regulatory axis and highlighted the Th17 cell differentiation and TCR signaling pathway, which might provide innovative molecular targets for therapeutic interventions for AS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02697-3.
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spelling pubmed-87289432022-01-06 Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis Xiao, Min Zheng, Xuqi Li, Xiaomin Wu, Xinyu Huang, Yefei Wei, Qiujing Cao, Shuangyan Gu, Jieruo Arthritis Res Ther Research Article BACKGROUND: The currently known risk loci could explain a small proportion of the heritability of ankylosing spondylitis (AS). Epigenetics might account for the missing heritability. We aimed to seek more novel AS-associated DNA methylation alterations and delineate the regulatory effect of DNA methylation and gene expression with integrated analysis of methylome and transcriptome. METHODS: Epigenome-wide DNA methylation and mRNA expression were profiled in peripheral blood mononuclear cells (PBMCs) from 45 individuals (AS: health controls (HCs) = 30:15) with high-throughput array. The methylome was validated in an independent cohort (AS: HCs = 12:12). Pearson correlation analysis and causal inference tests (CIT) were conducted to determine potentially causative regulatory effects of methylation on mRNA expression. RESULTS: A total of 4794 differentially methylated positions (DMPs) were identified associated with AS, 2526 DMPs of which were validated in an independent cohort. Both cohorts highlighted T cell receptor (TCR) signaling and Th17 differentiation pathways. Besides, AS patients manifested increased DNA methylation variability. The methylation levels of 158 DMPs were correlated with the mRNA expression levels of 112 genes, which formed interconnected network concentrated on Th17 cell differentiation and TCR signaling pathway (LCK, FYN, CD3G, TCF7, ZAP70, CXCL12, and PLCG1). We also identified several cis-acting DNA methylation and gene expression changes associated with AS risk, which might regulate the cellular mechanisms underlying AS. CONCLUSIONS: Our studies outlined the landscapes of epi-signatures of AS and several methylation-gene expression-AS regulatory axis and highlighted the Th17 cell differentiation and TCR signaling pathway, which might provide innovative molecular targets for therapeutic interventions for AS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02697-3. BioMed Central 2022-01-05 2022 /pmc/articles/PMC8728943/ /pubmed/34986893 http://dx.doi.org/10.1186/s13075-021-02697-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Xiao, Min
Zheng, Xuqi
Li, Xiaomin
Wu, Xinyu
Huang, Yefei
Wei, Qiujing
Cao, Shuangyan
Gu, Jieruo
Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis
title Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis
title_full Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis
title_fullStr Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis
title_full_unstemmed Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis
title_short Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis
title_sort integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of dna methylation in ankylosing spondylitis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728943/
https://www.ncbi.nlm.nih.gov/pubmed/34986893
http://dx.doi.org/10.1186/s13075-021-02697-3
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