Enhancer RNA-mediated gene regulation as a novel therapeutic strategy for autoimmune diseases 2527

Description Understanding gene expression regulation is crucial for therapeutic target discovery. Although enhancer RNAs (eRNAs) are implicated in regulation, their exact mechanisms remain unclear. We analyzed ChIP-seq and RNA-seq data to identify enhancers activated by LPS stimulation, confirming eRNA expression. ABC score analysis identified a specific enhancer regulating TNF-α and LT-α. To validate this enhancer’s function, we generated knockout mice targeting this region, observing modulation of TNF-α and LT-α expression. Using antisense oligonucleotides (ASOs) against eRNAs further confirmed their regulatory roles. Targeting eRNAs in rheumatoid arthritis (RA) and psoriasis mouse models showed disease amelioration. Notably, the this super-enhancer is conserved in humans, and ASO targeting in PBMCs from RA patients modulated TNF-α and LT-α expression. Lastly, we cataloged immune-response super-enhancer regions and associated eRNAs, offering therapeutic targets. Funding Sources This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (NRF-2023R1A2C1005804, RS-2024-00408822, RS-2024-00461521)