MLL1-pioneered H3K4me3 modification on KLF7 promoter accelerates the invasion of fibroblast-like synoviocytes in rheumatoid arthritis.

This study aims to elucidate the role of mixed lineage leukemia 1 (MLL1) in regulating the invasion of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA). RA-FLSs and HC-FLSs were isolated and cultured from synovial tissues of RA patients and healthy controls (HC). MLL1 knockdown was achieved in RA-FLSs using shRNA transfection. The expression of MLL1, Krüppel-like factor 7 (KLF7), and ubiquitin carboxyl-terminal hydrolase 7 (USP7) was assessed via quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell proliferation and invasion were evaluated using cell counting kit-8 (CCK-8) and Transwell assays. Chromatin immunoprecipitation (ChIP) assays were conducted to determine the enrichment of MLL1 and histone H3 lysine 4 trimethylation (H3K4me3) at the KLF7 promoter and the binding of KLF7 to the USP7 promoter. A dual-luciferase assay was used to validate the transcriptional activation of USP7 by KLF7. Results demonstrated that MLL1 was significantly overexpressed in RA-FLSs, and its inhibition suppressed FLS proliferation and invasion. Mechanistically, MLL1 promoted KLF7 transcription through H3K4me3 modification, and KLF7 subsequently upregulated USP7 expression. These findings reveal a novel MLL1/KLF7/USP7 regulatory axis that facilitates RA-FLS invasion and may represent a potential therapeutic target in RA.