Long noncoding RNA MANTIS facilitates endothelial angiogenic function

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 importa
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.
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Author:Matthias Leisegang, Christian Fork, Ivana Josipovic, Florian Martin Richter, Jens Preussner, Jiong Hu, Matthew J. Miller, Jeremy Epah, Patrick Hofmann, Stefan Günther, Franziska Moll, Chanil Valasarajan, Juliana Heidler, Yuliya Ponomareva, Thomas Michael Freiman, Lars Mägdefessel, Karl H. Plate, Michel Guy André Mittelbronn, Shizuka Uchida, Carsten Tobias Künne, Konstantinos Stellos, Ralph T. Schermuly, Norbert Weißmann, Kavi Devraj, Ilka Wittig, Reinier Boon, Stefanie Dimmeler, Soni Savai Pullamsetti, Mario Looso, Francis J. Miller, Ralf Peter Louis Brandes
URN:urn:nbn:de:hebis:30:3-439101
DOI:http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026991
ISSN:1524-4539
ISSN:0009-7322
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28351900
Parent Title (English):Circulation
Publisher:Lippincott, Williams & Wilkins ; Ovid
Place of publication:Philadelphia, Pa. ; [s. l.]
Document Type:Article
Language:English
Date of Publication (online):2017/10/19
Date of first Publication:2017/03/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/10/19
Tag:RNA, long noncoding; epigenomics; glioblastoma; hypertension, pulmonary; neovascularization, physiologic
Volume:136
Issue:1
Pagenumber:45
First Page:65
Last Page:79
Note:
© 2017 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
HeBIS PPN:427893372
Institutes:Medizin
Exzellenzcluster Makromolekulare Komplexe
Sonderforschungsbereiche / Forschungskollegs
DFG-Forschergruppen
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0

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