Downregulation of lncRNA EPB41L4A-AS1 Mediates Activation of MYD88-Dependent NF-κB Pathway in Diabetes-Related Inflammation
Authors Wang Z, Liao W, Liu F, Yang T, Xie W, Liao M, Gu D, Zhang Y
Received 6 September 2020
Accepted for publication 30 December 2020
Published 20 January 2021 Volume 2021:14 Pages 265—277
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Juei-Tang Cheng
Ziqing Wang,1,2 Weijie Liao,2,3 Fuhai Liu,2,4 Tingpeng Yang,2 Weidong Xie,2,3 Meijian Liao,3,4 Dayong Gu,5 Yaou Zhang2,3
1School of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China; 2State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, People’s Republic of China; 3Key Laboratory in Healthy Science and Technology, Division of Life Science, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, People’s Republic of China; 4Department of Pathology, Xuzhou Medical University, Xuzhou 221104, People’s Republic of China; 5Department of Laboratory Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People’s Republic of China
Correspondence: Yaou Zhang
State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, People’s Republic of China
Department of Laboratory Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People’s Republic of China
Purpose: Long non-coding RNAs (lncRNAs) have been shown to be involved in many human diseases. In this study, we aimed to reveal the role and molecular mechanism of lncRNA EPB41L4A-AS1 in type 2 diabetic mellitus (T2DM)-related inflammation.
Methods: To explore the relationships between the expression of EPB41L4A-AS1 and inflammatory factors in the blood of T2DM patients, we analyzed peripheral blood mononuclear cell (PBMC) expression microarrays of T2DM patients and expression microarrays of PBMC treated with lipopolysaccharide (LPS) from the GEO database. The relationship between EPB41L4A-AS1 and phospho-p65 was explored by Western blotting (WB) and immunofluorescence. The interactions between EPB41L4A-AS1 and myeloid differentiation factor 88 (MYD88) were also verified through quantitative real-time PCR, WB, and chromatin immunoprecipitation. Glycolysis and mitochondrial stress were detected by Seahorse.
Results: EPB41L4A-AS1 showed very low expression, which was significantly negatively correlated with levels of inflammatory factors in PBMCs of T2DM patients and PBMCs treated with LPS. These results were verified by cell experiments on PBMC and THP-1 cells. Knockdown of EPB41L4A-AS1 led to the phosphorylation and nuclear translocation of p65 and thus activated the NF-κB signaling pathway; it also reduced the enrichment of H3K9me3 in the MYD88 promoter and increased expression of MYD88. Overall, EPB41L4A-AS1 knockdown promoted the level of glycolysis and ultimately enhanced the inflammatory response.
Conclusion: EPB41L4A-AS1 knockdown activated the NF-κB signaling pathway through a MYD88-dependent regulatory mechanism, promoted glycolysis, and ultimately enhanced the inflammatory response. These results demonstrate that EPB41L4A-AS1 is closely associated with inflammation in T2DM, and that low expression of EPB41L4A-AS1 may be used as an indicator of chronic inflammation and possible diabetic vascular complications in T2DM patients.
Keywords: inflammation, diabetes, EPB41L4A-AS1, NF-κB, MYD88
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