Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting

Abstract

Background and objectiveSystemic 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.MethodsChromatin 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.Results1046 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.ConclusionSSc 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.

The Long Non-coding RNA NRIR Drives IFN-Response in Monocytes: Implication for Systemic Sclerosis

“…To verify whether the selected “IFN/viral” lncRNAs were effectively related to the IFN signature in an in vivo setting where the IFN pathway is known to play a pathogenetic role, the expression level of the 99 selected lncRNAs was then retrieved and analyzed from the transcriptomic profile of monocytes purified from the “definite SSc” (35) and “non-fibrotic SSc” cohorts of patients and matched healthy donors (Tables 1, 2). The patient cohorts included individuals presenting with different SSc phenotypes according to clinical features and the extent of skin fibrosis, i.e., early SSc (eaSSc, n = 11), non-cutaneous SSc (ncSSc, n = 17), limited cutaneous SSc (lcSSc, n = 11), diffuse cutaneous SSc (dcSSc, n = 7).…”

“…RNA sequencing data of peripheral blood monocytes purified from SSc, together with sex- and age-matched healthy controls (HC) enrolled in the “definite SSc” cohort, were obtained from the University Medical Center Utrecht (UMCU), The Netherlands (35).…”

The contribution of epigenetics to the pathogenesis and gender dimorphism of systemic sclerosis: a comprehensive overview

“…48 Besides fibroblasts and B cells, histone modifications at a genome-wide level have been implicated in the altered phenotype of SSc monocytes. 49 An indirect role of histone deacetylation in the fibrotic process of SSc has been suggested based on the evidence that treatment of SSc skin fibroblasts with trichostatin A suppressed TGF-βinduced mRNA expression of type I collagen and fibronectin and prevented dermal deposition of extracellular matrix in experimental scleroderma. 63 The contribution of histone acetylation to SSc pathogenesis is further supported by aberrant cell-specific expression patterns of the histone-modifying enzymes regulating this epigenetic process.…”

Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases

“…Within epigenetic modifications, microRNA (miRNAs) analyses have been performed in several IIMs, such as dermatomyositis and polymyositis, proposing them as potential targets for diagnosis and treatment [20]. On the other hand, Kroef and colleagues demonstrated the influence of H3K27ac and H3K27ac histone modifications in the expression of genes related to IFN and cytokines signaling pathways in monocytes of SSc patients, highlighting these as promising for the treatment of SSc [21].…”