Background and objective Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes.
Methods Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression.
Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression.
Conclusion SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.
- systemic sclerosis
- histone modification
- epigenetic targeting
Statistics from Altmetric.com
TRDJR and MR contributed equally.
Handling editor Josef S Smolen
Contributors MR designed and supervised the study. MvdK, MR, MCo and TRDJR wrote the manuscript. MvdK and MCo performed the experiments. MvdK, MR, MCo, MCa, EC, CGKW, LB, ET, SSC, NV, TC, CA, CPJB, FBM, EJMZ and AJA collected samples and analysed the data. MG, MM, LMBC, KAR and FB collected, analysed and supplied (clinical) data. All authors have critically revised the manuscript for important intellectual content.
Funding This work was funded by the Dutch Arthritis Foundation (Reuma Nederland) grant number NR14-3-403.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study was approved by the board of the Local Medical Ethical Committee (METC).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement RNA-sequencing data presented in this study have been deposited in NCBI’s Gene Expression Omnibus (GEO) database under GEO: GSE124073 (Linked to GSE124075) The ChIP-seq data presented in this study have been deposited in NCBI’s Gene Expression Omnibus (GEO) database under GEO: GSE124070 (linked to GESE124075). Further data requests can be addressed to the corresponding author.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.