Long non-coding RNA-gm33782 exacerbates acute kidney injury by upregulating the PA1-MLL3/MLL4 complex and promoting histone H3 lysine 4 monomethylation-dependent forkhead box O3 enhancer activation

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As a common clinical syndrome with high morbidity and mortality, acute kidney injury (AKI) involves epigenetic mechanisms that remain largely uncharacterized. In this study, we identify a previously uncharacterized long non-coding RNA mmu-lncR-gm33782 and its human homolog hsa-lncR-CLLU1-AS1 as a critical epigenetic driver of AKI. We found that LncR-gm33782 was markedly upregulated in AKI kidneys, and its genetic ablation substantially alleviated tubular injury and inflammation. Transcriptomic profiling revealed that lncR-gm33782 overexpression broadly upregulated genes encoding components of the PA1-MLL3/4 methyltransferase complex. Mechanistically, lncR-gm33782 functionally engages the PAXIP1 associated glutamate rich protein 1 (PA1) promoter to enhance PA1 transcription. Elevated PA1 facilitated recruitment of the Lysine methyltransferase 2C and lysine methyltransferase 2D (MLL3/MLL4) complex to an intronic enhancer within the Forkhead box O3 (Foxo3) locus, leading to increased histone H3 lysine 4 monomethylation (H3K4me1) and histone H3 lysine 27 acetylation (H3K27ac) deposition. Consequently, Foxo3 expression was activated and established a positive autoregulatory loop that further amplified its expression. In vivo, locked nucleic acid modified antisense oligonucleotide (ASO) mediated knockdown attenuated AKI induced renal injury while concomitantly suppressing PA1 and Foxo3 expression. Notably, the human homolog hsa-lncR-CLLU1-AS1 was consistently upregulated in the blood of AKI patients and positively associated with serum creatinine as well as blood urea nitrogen. Our findings uncover a conserved lncRNA-PA1-MLL3/4-Foxo3 epigenetic axis that drives enhancer reprogramming and a self-reinforcing Foxo3 circuit. These findings position this lncRNA as a promising therapeutic target and its human homolog as a circulating biomarker for AKI.

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