Diabetes Mellitus-Induced Long Noncoding RNA Dnm3os Regulates Macrophage Functions and Inflammation via Nuclear Mechanisms
| Autor: | Sadhan Das, Dustin E. Schones, Sridevi Devaraj, Marpadga A. Reddy, Parijat Senapati, Kenneth Stapleton, Mei Wang, Vishnu Amaram, Linda Lanting, Rama Natarajan, Rituparna Ganguly, Lingxiao Zhang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Mice Knockout ApoE Inflammation 030204 cardiovascular system & hematology Streptozocin Diabetes Mellitus Experimental Epigenesis Genetic 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Phagocytosis medicine Animals Humans Gene Cell Nucleus Gene knockdown Chemistry Macrophages RNA RNA-Binding Proteins Macrophage Activation Phosphoproteins Cell biology Chromatin Up-Regulation Mice Inbred C57BL 030104 developmental biology Diabetes Mellitus Type 1 Phenotype RAW 264.7 Cells Diabetes Mellitus Type 2 Case-Control Studies Female RNA Long Noncoding medicine.symptom Inflammation Mediators Cardiology and Cardiovascular Medicine Chromatin immunoprecipitation Nucleolin Protein Binding Signal Transduction |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 38(8) |
| ISSN: | 1524-4636 |
| Popis: | Objective— Macrophages play key roles in inflammation and diabetic vascular complications. Emerging evidence implicates long noncoding RNAs in inflammation, but their role in macrophage dysfunction associated with inflammatory diabetic complications is unclear and was therefore investigated in this study. Approach and Results— RNA-sequencing and real-time quantitative PCR demonstrated that a long noncoding RNA Dnm3os (dynamin 3 opposite strand) is upregulated in bone marrow-derived macrophages from type 2 diabetic db/db mice, diet-induced insulin-resistant mice, and diabetic ApoE −/− mice, as well as in monocytes from type 2 diabetic patients relative to controls. Diabetic conditions (high glucose and palmitic acid) induced Dnm3os in mouse and human macrophages. Promoter reporter analysis and chromatin immunoprecipitation assays demonstrated that diabetic conditions induce Dnm3os via NF-κB activation. RNA fluorescence in situ hybridization and real-time quantitative PCRs of subcellular fractions demonstrated nuclear localization and chromatin enrichment of Dnm3os in macrophages. Stable overexpression of Dnm3os in macrophages altered global histone modifications and upregulated inflammation and immune response genes and phagocytosis. Conversely, RNAi-mediated knockdown of Dnm3os attenuated these responses. RNA pull-down assays with macrophage nuclear lysates identified nucleolin and ILF-2 (interleukin enhancer-binding factor 2) as protein binding partners of Dnm3os , which was further confirmed by RNA fluorescence in situ hybridization immunofluorescence. Furthermore, nucleolin levels were decreased in diabetic conditions, and its knockdown enhanced Dnm3os -induced inflammatory gene expression and histone H3K9-acetylation at their promoters. Conclusions— These results demonstrate novel mechanisms involving upregulation of long noncoding RNA Dnm3os , disruption of its interaction with nucleolin, and epigenetic modifications at target genes that promote macrophage inflammatory phenotype in diabetes mellitus. The data could lead to long noncoding RNA-based therapies for inflammatory diabetes mellitus complications. |
| Databáze: | OpenAIRE |
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