Targeting eRNA-Producing Super-Enhancers Regulates TNFα Expression and Mitigates Chronic Inflammation in Mice and...

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Chronic inflammatory diseases involve immune cell dysregulation and elevated pro-inflammatory molecules like tumor necrosis factor alpha (TNFα).
• Super-enhancers (SEs) and their enhancer RNAs (eRNAs) are key regulators of gene expression with therapeutic potential.
• Targeting eRNAs presents a novel strategy beyond traditional protein-targeting therapies for inflammation.

Purpose of the Study:

• To investigate the therapeutic potential of targeting TNFα-regulating eRNAs to reduce chronic inflammation.
• To explore eRNAs as druggable targets for inflammatory diseases.

Main Methods:

• Generation of TNF-9 knockout (KO) mice lacking a Tnfα-regulating enhancer region.
• Integrative epigenomic and transcriptomic analyses to identify additional eRNA targets.
• Antisense oligonucleotide (ASO)-mediated knockdown of TNF-9 eRNA in mouse macrophages and human cells.

Main Results:

• TNF-9 KO mice showed significantly reduced Tnfα levels, improved disease outcomes in rheumatoid arthritis (RA), psoriasis, and sepsis models.
• Epigenomic analysis identified novel LPS-responsive eRNA-producing enhancers.
• ASO-mediated eRNA knockdown decreased Tnfα expression and alleviated RA symptoms in mice and human cells.

Conclusions:

• Targeting TNFα-regulating eRNAs is a viable therapeutic strategy for chronic inflammatory diseases.
• eRNA-targeted interventions demonstrate efficacy in preclinical models, offering a new treatment avenue.