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Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186199 | GEO | 2023/03/22

REPOSITORIES: GEO

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Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis [RNA-seq]

Project description:Objectives: To identify key pathways, transcriptional regulators and epigenetic mechanisms underlying conventional dendritic cell (cDC) alteration in Systemic Sclerosis (SSc). Methods: Transcriptomic profiling was performed on CD1c+ cDCs isolated from peripheral blood samples obtained from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using the Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays. Results: We identified 17 modules of co-expressed genes in cDCs that correlated with SSc subtypes and key clinical traits. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype suffering from severe fibrosis. Gene regulatory network analysis performed on the immune regulatory module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the master transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis of cDCs supported that these NR4A members target numerous differentially expressed genes in SSc cDCs. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDCs and modulates T-cells activation. Conclusions: NR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.

2023-03-22 | GSE186198 | GEO

Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis [ChIP-seq]

2023-03-22 | GSE186197 | GEO