Long noncoding RNA MANTIS facilitates endothelial angiogenic function
| Autor: | Konstantinos Stellos, Ralph T. Schermuly, Stefan Günther, Matthias S. Leisegang, Yuliya Ponomareva, Ilka Wittig, Carsten Künne, Ralf P. Brandes, Lars Maegdefessel, Patrick Hofmann, Christian Fork, Franziska Moll, Stefanie Dimmeler, Jeremy Epah, Reinier A. Boon, Jiong Hu, Chanil Valasarajan, Jens Preussner, Shizuka Uchida, Florian Richter, Mario Looso, Juliana Heidler, Thomas M. Freiman, Francis J. Miller, Soni Savai Pullamsetti, Karl H. Plate, Ivana Josipovic, Matthew J. Miller, Kavi Devraj, Norbert Weissmann, Michel Mittelbronn |
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| Přispěvatelé: | Physiology, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Jumonji Domain-Containing Histone Demethylases Hypertension Pulmonary Neovascularization Physiologic Mice SCID 030204 cardiovascular system & hematology Biology DNA-binding protein Chromatin remodeling Cell Line Epigenesis Genetic Rats Sprague-Dawley Neovascularization Mice 03 medical and health sciences 0302 clinical medicine Physiology (medical) Human Umbilical Vein Endothelial Cells medicine Animals Humans Epigenetics ddc:610 COUP-TFII Epigenomics Nuclear Proteins Molecular biology Long non-coding RNA Rats Cell biology Repressor Proteins Macaca fascicularis 030104 developmental biology Microvessels RNA Long Noncoding CRISPR-Cas Systems medicine.symptom Cardiology and Cardiovascular Medicine Function (biology) |
| Zdroj: | Leisegang, M S, Fork, C, Josipovic, I, Richter, F M, Preussner, J, Hu, J, Miller, M J, Epah, J, Hofmann, P, Günther, S, Moll, F, Valasarajan, C, Heidler, J, Ponomareva, Y, Freiman, T M, Maegdefessel, L, Plate, K H, Mittelbronn, M, Uchida, S, Künne, C, Stellos, K, Schermuly, R T, Weissmann, N, Devraj, K, Wittig, I, Boon, R A, Dimmeler, S, Pullamsetti, S S, Looso, M, Miller, F J & Brandes, R P 2017, ' Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function ', Circulation, vol. 136, no. 1, pp. 65-79 . https://doi.org/10.1161/CIRCULATIONAHA.116.026991 Circulation, 136(1), 65-79. Lippincott Williams and Wilkins |
| ISSN: | 0009-7322 |
| Popis: | Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs. Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression. Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18 , SMAD6 , and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding. Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function. |
| Databáze: | OpenAIRE |
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