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

2022 ◽  
Vol 24 (1) ◽  
Author(s):  
Min Xiao ◽  
Xuqi Zheng ◽  
Xiaomin Li ◽  
Xinyu Wu ◽  
Yefei Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Differentiation ◽  
Ankylosing Spondylitis ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Th17 Cell ◽  
Tcr Signaling ◽  
Th17 Cell Differentiation ◽  
Independent Cohort

Abstract 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.

Identification of early gene expression changes during human Th17 cell differentiation

Blood ◽  
2012 ◽  
Vol 119 (23) ◽  
pp. e151-e160 ◽  
Author(s):  
Soile Tuomela ◽  
Verna Salo ◽  
Subhash K. Tripathi ◽  
Zhi Chen ◽  
Kirsti Laurila ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Early Gene ◽  
Th17 Cell Differentiation ◽  
Genome Wide ◽  
Starting Point ◽  
Th17 Differentiation

Abstract Th17 cells play an essential role in the pathogenesis of autoimmune and inflammatory diseases. Most of our current understanding on Th17 cell differentiation relies on studies carried out in mice, whereas the molecular mechanisms controlling human Th17 cell differentiation are less well defined. In this study, we identified gene expression changes characterizing early stages of human Th17 cell differentiation through genome-wide gene expression profiling. CD4+ cells isolated from umbilical cord blood were used to determine detailed kinetics of gene expression after initiation of Th17 differentiation with IL1β, IL6, and TGFβ. The differential expression of selected candidate genes was further validated at protein level and analyzed for specificity in initiation of Th17 compared with initiation of other Th subsets, namely Th1, Th2, and iTreg. This first genome-wide profiling of transcriptomics during the induction of human Th17 differentiation provides a starting point for defining gene regulatory networks and identifying new candidates regulating Th17 differentiation in humans.

scholarly journals Th17 Cell Differentiation Induced by Cytopathogenic Biotype BVDV-2 in Bovine PBLCs

2021 ◽  
Author(s):  
Yanping Li ◽  
Tingli Liu ◽  
Guoliang Chen ◽  
Liqun Wang ◽  
Aimin Guo ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Signaling Pathway ◽  
Th17 Cell ◽  
Bovine Viral Diarrhea ◽  
Control Group ◽  
Sequencing Analysis ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Th17 Cell Differentiation ◽  
Transcriptomic Sequencing

Abstract Background: Bovine viral diarrhea virus (BVDV) is a major pathogen that causes bovine viral diarrhea/mucosal disease (BVD-MD), which has become a global infectious disease due to its wide spread and the lack of effective treatment. The process of BVDV infection is complex. Once infected, host immune cells are activated and modulated. As a major immune cell, peripheral blood lymphocyte cells (PBLCs) are the primary target of BVDV. In order to further understand the mechanism of BVDV- host interaction, the expression profiles of host lymphocytes mRNAs associated with BVDV infection were investigated by transcriptomic sequencing analysis. Results: The transcriptomic sequencing analysis was performed on bovine PBLCs infected with CP BVDV-2 GS2018 after 12 h of infection. Gene expression profiling demonstrated that 1,052 genes were differentially expressed in GS2018 infected PBLCs compared with the control group. Of these genes, 485 genes were up-regulated and 567 were down-regulated. 19 differential expressed genes (DEGs) were selected for validation using quantitative real-time PCR and the results were consistent with the results of RNA-Seq. Gene ontology enrichment and KEGG pathway analysis showed that 1052 DEGs were significantly enriched in 16 pathways, including cytokine-cytokine receptor interaction, IL17 signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway and TNF signaling pathway. PPI network analysis showed that IL17A, IFN-γ and TNF-α interacted with various proteins and may play crucial roles in BVDV-2 infection. Of note, we confirmed that GS2018 induced Th17 cell differentiation in PBLCs and persistently increased the expression levels of IL17A. In turn, the replication of GS2018 was inhibited by IL17A. Conclusion: In this study, the transcription changes of DEGs related to host immune responses in bovine PBLCs were caused by CP BVDV-2 infection. In particular, the effector molecules IL17A of Th17 cells were significantly up-regulated, which inhibited viral replication. These results will contribute to exploration and further understanding of the host immune response mechanism and interaction between host and BVDV-2.

scholarly journals Immune Regulation of TNFAIP3 in Psoriasis through Its Association with Th1 and Th17 Cell Differentiation and p38 Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yanyun Jiang ◽  
Wenming Wang ◽  
Xiaofeng Zheng ◽  
Hongzhong Jin
Keyword(s):  
Cell Differentiation ◽  
Mouse Model ◽  
Mrna Expression ◽  
Immune Regulation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Serum Levels ◽  
Control Group ◽  
Expression Levels ◽  
Th17 Cell Differentiation

Background. Psoriasis is an immune-mediated chronic inflammatory skin disorder in which the dysregulation of immune cells plays an important role in its development. Tumor necrosis factor- (TNF-) α antagonists affect the immune repertoire, while TNF-α-induced protein 3 (TNFAIP3) has a protective role against the deleterious effects of inflammation and participates in immune regulation. Objective. We investigated the immune regulation of TNFAIP3 in the pathogenesis of psoriasis and determined whether it is involved in the antipsoriatic effect of TNF-α antagonists. Methods. mRNA levels were evaluated in blood from patients with moderate-to-severe psoriasis. The effects of TNF-α antagonists were examined in a mouse imiquimod- (IMQ-) induced psoriasis-like dermatitis model. In the mouse model, TNFAIP3 mRNA expression was determined using RT-PCR. Serum levels of IL-17A, IL-23, IFN-γ, TNF-α, phosphorylated ERK1/2, p38, and JNK were measured using ELISA. The proportion of Th1 and Th17 cells in mouse spleens was analyzed using flow cytometry. Results. mRNA expression levels of TNFAIP3 in the blood were significantly lower in patients with moderate and severe psoriasis (mean±SD=0.44±0.25) compared with normal subjects (mean±SD=1.00±0.82) (P<0.01). In the mouse model, IMQ downregulated TNFAIP3 expression levels, which were increased after TNF-α antagonist treatment (P<0.05). Serum levels of Th17 cytokines (IL-17A and IL-23) and Th1 cytokines (IFN-γ and TNF-α) were significantly higher in the IMQ and IMQ/rat IgG1 groups compared with the control group, and the application of TNF-α antagonists significantly decreased the levels of inflammatory cytokines (P<0.01). Notably, phosphorylated p38 levels were increased in the IMQ and IMQ/rat IgG1 groups compared with the control group but were downregulated by treatment with TNF-α antagonists (P<0.05). Th1 and Th17 cells were significantly increased in the IMQ group compared with the control group (P<0.01). Conclusion. TNFAIP3 downregulation associated with Th1 and Th17 cell differentiation and p38 activation might contribute in part to the mechanism of immune dysfunction in psoriasis. TNF-α antagonists might partly exert their effects on psoriasis via this pathway.

scholarly journals Analysis of mRNA Expression and DNA Methylation Datasets According to the Genomic Distribution of CpG Sites in Osteoarthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Yi ◽  
Xiongfeng Xu ◽  
Jiawei Yao ◽  
Bo Qiu
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Regulation Of Gene Expression ◽  
Enrichment Analysis ◽  
Integrated Analysis ◽  
Mrna Levels ◽  
Combined Analysis ◽  
Transcriptional Changes

Abstract Objectives Transcriptional changes in cartilage can impact function by causing degradation such as that which occurs during the development of osteoarthritis (OA). Epigenetic regulation may be a key factor leading to transcriptional changes in OA. In this study, we performed a combined analysis of DNA methylation and gene expression microarray datasets and identified key transcription factors (TFs) central to the regulation of gene expression in OA. Methods A DNA methylation profile dataset (GSE63106) and a gene expression profiling dataset (GSE114007) were extracted from the Gene Expression Omnibus (GEO). We used ChAMP methylation analysis and the Limma package to identify differentially methylation genes (DMGs) and differentially expressed genes (DEGs) from normal and human knee cartilage samples in OA. Function enrichment analysis of DMGs was conducted using the DAVID database. A combined analysis of DEGs and DMGs was conducted to identify key TFs in OA. We then validated the mRNA expression of selected TFs in normal and OA cartilage by RT-qPCR. Primary chondrocytes were cultured and treated with the DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza) for functional validation. Results We identified 2,170 differential methylation sites (DMS) containing 1005 genes and 1986 DEGs between normal human and OA cartilage. Functional analysis of DMGs revealed that focal adhesion, extracellular matrix (ECM)-receptor interactions, the PI3K-Akt signaling pathway, and the FoxO signaling pathway were involved in OA. Integrated analysis showed a subset of 17 TFs. Four TFs (ELF3, SOX11, RARA, and FOXD2) were validated. RT-qPCR results showed the mRNA expression of SOX11, RARA, and FOXD2 were consistent with the results from the mRNA expression data. However, the expression of ELF3 could not be validated. Upon 5-Aza-2′-deoxycytidine (5-Aza) treatment, the mRNA levels of ELF3 and SOX11 were down-regulated, whilst RARA was up-regulated, and FOXD2 showed no significant change in expression level. Conclusions the effect of DNA methylation on the transcriptional regulation is related to the distribution of methylated sites across the genome. Epigenetic studies on the positions of DMS in transcriptional units can inform a better understanding of the function of DNA methylation and its transcription regulation.

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