Loss of H3K9 di-methylation perpetuates the type I interferon signature in SLE and is pharmacologically reversible by ribavirin
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Background
Systemic lupus erythematosus (SLE) is characterised by a chronic type I interferon (IFN) signature whose epigenetic basis remains incompletely defined. Histone H3 lysine 9 dimethylation (H3K9me2) is a key repressive mark that can shape DNA-methylation landscapes and antiviral responses.
Methods
Naïve CD4⁺ T cells were purified from 29 adults with SLE and 15 healthy donors. Genome-wide distributions of H3K9me2 and, for comparison, H3K27me3 were mapped by Cleavage Under Targets and Tagmentation (CUT&Tag). Targeted chromatin immunoprecipitation-qPCR and quantitative RT-PCR validated findings at canonical interferon-stimulated genes (ISGs). Pharmacological rescue was tested ex-vivo with ribavirin (RBV) ± the G9a inhibitor BIX01294. Therapeutic relevance was assessed in NZB/W-F1 lupus-prone mice treated with RBV (50–250 mg kg⁻¹, i.p., twice weekly for 20 weeks).
Results
CUT&Tag revealed a pronounced, genome-wide reduction of H3K9me2—but not H3K27me3—in SLE T cells, which segregated cases from controls by principal-component analysis. H3K9me2 loss was most evident across ISG loci and inversely correlated with ISG mRNA expression. In vitro, RBV restored H3K9me2 at ISG regions and repressed ISG transcripts; both effects were abrogated by G9a inhibition, implicating G9a-dependent dimethylation. In NZB/W-F1 mice, RBV dose-dependently reduced proteinuria, diminished renal immune-complex deposition, and normalised splenic CD4⁺ T-cell ISG expression, mirroring ex-vivo epigenetic rescue.
Conclusions
Loss of H3K9me2 is a selective epigenetic lesion that sustains the type I IFN signature in SLE. Pharmacological reinstatement of this mark with ribavirin reverses aberrant ISG activation and ameliorates lupus nephritis in vivo, highlighting H3K9me2 restoration as a tractable therapeutic strategy for IFN-high SLE.
