LncRNA NKILA regulates endothelium inflammation by controlling a NF-κB/KLF4 positive feedback loop

• Published in: Journal of molecular and cellular cardiology 2019-01, Vol.126, p.60-69
• Main Authors: Zhu, Xinxing, Du, Jiang, Yu, Jinjin, Guo, Rui, Feng, Yanyan, Qiao, Liang, Xu, Zhihao, Yang, Fen, Zhong, Genshen, Liu, Fulong, Cheng, Fangfang, Chu, Maoping, Lin, Juntang
• Format: Article
• Language: English
• Subjects: DNA (Cytosine-5-)-Methyltransferases; DNA Methylation - genetics; Endothelium inflammation; Endothelium, Vascular - pathology; Feedback loop; Feedback, Physiological; Gene Expression Regulation; HEK293 Cells; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Inflammation - genetics; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Methylation; Models, Biological; NF-kappa B - metabolism; NKILA; Promoter Regions, Genetic - genetics; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Transcription, Genetic
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2018.11.001

Endothelium inflammation, a key event in vascular pathological process, can lead to endothelial activation and subsequent vascular disorders. Long non-coding RNA NKILA plays an important regulatory role in pro-inflammatory response. However, the underlying molecular basis by which NKILA regulates endothelial inflammation is poorly understood. In this study, we identify NKILA as a critical repressor to protect the endothelium from inflammation. Mechanistically, we show that NKILA is able to positively mediate the expression of KLF4, an anti-inflammatory atheroprotective regulator in endothelial cells (ECs), by a NF-κB-mediated DNA methylation mechanism. Moreover, NF-κB is found to help recruit DNMT3A to the CpG island of KLF4 promoter, facilitating KLF4 promoter DNA methylation and transcriptional repression. More importantly, we find KLF4 can inversely attenuate NF-κB transcriptional activity via establishing a NF-κB/KLF4 positive feedback loop, which is under the control of NKILA. Hence, sustained endothelium inflammation will occur, once the NKILA becomes dysfunctional. These studies revealed that NKILA can function as a vital regulator to protect the endothelium from inflammatory lesions and related vascular diseases. •The lncRNA NKILA functions as critical repressor for endothelium inflammation and has a significant correlation with carotid artery atherosclerosis.•NKILA can epigenetically regulate the expression of the atheroprotective regulator KLF4 by a NF-κB-mediated DNA methylation mechanism.•Attenuation of KLF4 can inversely elevate the NF-κB activity by establishing a positive feedback loop, which is under the control of NKILA.