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Targeting eRNA-producing super-enhancers regulates TNFα expression and mitigates chronic inflammation in mice and patient-derived immune cells [RNA-KO]

ABSTRACT: Chronic inflammatory diseases are driven by immune cell dysregulation and overproduction of pro-inflammatory molecules, such as tumor necrosis factor alpha (TNFα). Super-enhancers (SEs) and their enhancer RNAs (eRNAs) are critical gene expression regulators and offer therapeutic potential beyond protein-targeting approaches. We hypothesized that targeting eRNAs could reduce chronic inflammation by modulating TNFα expression. We generated TNF-9 knockout (KO) mice by deleting a Tnfα-regulating enhancer region. These mice exhibited significantly reduced Tnfα levels, improved disease outcomes, and diminished immune cell activation in models of rheumatoid arthritis (RA), psoriasis, and lipopolysaccharide (LPS)-induced sepsis. Integrative epigenomic and transcriptomic analysis identified additional LPS-responsive, eRNA-producing enhancers as therapeutic targets. Antisense oligonucleotide (ASO)-mediated knockdown of TNF-9 eRNA in mouse macrophages demonstrated decreased Tnfα expression and alleviated RA symptoms. Furthermore, ASO-mediated inhibition of the eRNA of the human homolog of TNF-9 similarly reduced TNFα levels. These findings support eRNA-targeted interventions as potential treatment for chronic inflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE291300 | GEO | 2025/03/11

REPOSITORIES: GEO

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Targeting eRNA-producing super-enhancers regulates TNFα expression and mitigates chronic inflammation in mice and patient-derived immune cells [CUT&RUN]

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