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2017 ; 136
(1
): 65-79
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Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function
#MMPMID28351900
Leisegang MS
; Fork C
; Josipovic I
; Richter FM
; Preussner J
; Hu J
; Miller MJ
; Epah J
; Hofmann P
; Günther S
; Moll F
; Valasarajan C
; Heidler J
; Ponomareva Y
; Freiman TM
; Maegdefessel L
; Plate KH
; Mittelbronn M
; Uchida S
; Künne C
; Stellos K
; Schermuly RT
; Weissmann N
; Devraj K
; Wittig I
; Boon RA
; Dimmeler S
; Pullamsetti SS
; Looso M
; Miller FJ Jr
; Brandes RP
Circulation
2017[Jul]; 136
(1
): 65-79
PMID28351900
show ga
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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