TY  - JOUR
A1  - Leisegang, Matthias
A1  - Fork, Christian
A1  - Josipovic, Ivana
A1  - Richter, Florian Martin
A1  - Preussner, Jens
A1  - Hu, Jiong
A1  - Miller, Matthew J.
A1  - Epah, Jeremy
A1  - Hofmann, Patrick
A1  - Günther, Stefan
A1  - Moll, Franziska
A1  - Valasarajan, Chanil
A1  - Heidler, Juliana
A1  - Ponomareva, Yuliya
A1  - Freiman, Thomas Michael
A1  - Mägdefessel, Lars
A1  - Plate, Karl
A1  - Mittelbronn, Michel Guy André
A1  - Uchida, Shizuka
A1  - Künne, Carsten Tobias
A1  - Stellos, Konstantinos
A1  - Schermuly, Ralph T.
A1  - Weißmann, Norbert
A1  - Devraj, Kavi
A1  - Wittig, Ilka
A1  - Boon, Reinier
A1  - Dimmeler, Stefanie
A1  - Pullamsetti, Soni Savai
A1  - Looso, Mario
A1  - Miller, Francis J.
A1  - Brandes, Ralf
T1  - Long noncoding RNA MANTIS facilitates endothelial angiogenic function
T2  - Circulation
N2  - 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.
KW  - RNA, long noncoding
KW  - epigenomics
KW  - glioblastoma
KW  - hypertension, pulmonary
KW  - neovascularization, physiologic
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/43910
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-439101
SN  - 1524-4539
SN  - 0009-7322
N1  - © 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.
VL  - 136
IS  - 1
SP  - 65
EP  - 79
PB  - Lippincott, Williams & Wilkins ; Ovid
CY  - Philadelphia, Pa. ; [s. l.]
ER  -