Loss of epigenetic memory reactivates cell-type specific, proinflammatory transposons in patients with systemic sclerosis

• Applicants: Professor Dr. Jörg Hans Wilhelm Distler; Professor Dr. Armando Gabrielli
• Subject Area: Rheumatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551691366

Aberrant immune responses to particular cells or tissues, followed by an increase in this immune response, are a common hallmark of the pathophysiology of autoimmune disorders. In individuals with autoimmune disorders, the presence of interferon (IFN) and NFkappaB signatures is a common manifestation of this abnormal immune response. Recently, reactivation of the expression of numerous types of silenced transposons (TEs) has emerged as a molecular pattern in autoimmune diseases including systemic sclerosis (SSc). Mobile genetic elements, or TEs, are integrated into the human genome from mutant viruses. Epigenetic processes closely regulate TEs because their expression induces inflammation. The silencing of TEs under physiological settings is permanent and steady, with the exception of a brief reactivation period during development. But under circumstances like inflammation, which are linked to cellular stress, TEs' epigenetic regulation may become less restrictive and allow for their reexpression. Reactivated TEs promote the amplification of IFN-NFkappaB signals, which are important triggers for inflammatory reactions. We postulated that pathologic reactivation of TE expression in SSc patients may be partially responsible for the interferon type I signature that is frequently seen in these individuals. In fact, we observed in a preliminary analysis that CD4 and CD8 T lymphocytes of SSc patients express several TEs with significant quantitative differences compared to healthy individuals. Many of these TEs were also expressed in skin SSc biopsies. Of note, TEs in SSc were different from TEs found in CD4 T cells of patients with multiple sclerosis (MS), suggesting disease-specific patterns of TE reactivation. In the proposed study, we aim to perform 1.) a genome-wide DNA methylation analysis of different cell types from SSc patients and healthy individuals, 2.) deep RNA sequencing to identify the TE families and the relative single-copy genes associated with the TE in the genome, 3.) chromatin ATAC and ChIP seq with antibodies to histone H3 repressive (H3K9me3-H3K27 me3) and activation (H3K4me3-H3K27 acetylated) markers to establish whether the reactivation is cell-specific, TE-specific or TE family-specific, 4.) functional studies of the role of the main TEs differentially expressed in SSc cells using CRISPR-CAS9 technology and 5.) association studies of TE reactivation with clinical phenotypes and disease outcomes.

• DFG Programme: Research Grants