Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function

Matthias S. 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 M. Freiman; Lars Maegdefessel; Karl H. Plate; Michel Mittelbronn; Shizuka Uchida; Carsten Künne; Konstantinos Stellos; Ralph T. Schermuly; Norbert Weissmann; Kavi Devraj; Ilka Wittig; Reinier A. Boon; Stefanie Dimmeler; Soni Savai Pullamsetti; Mario Looso; Francis J. Miller; Ralf P. Brandes

doi:10.1161/CIRCULATIONAHA.116.026991

Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function

Matthias S. 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 M. Freiman, Lars Maegdefessel, Karl H. Plate, Michel Mittelbronn, Shizuka Uchida, Carsten KünneKonstantinos Stellos, Ralph T. Schermuly, Norbert Weissmann, Kavi Devraj, Ilka Wittig, Reinier A. Boon, Stefanie Dimmeler, Soni Savai Pullamsetti, Mario Looso, Francis J. Miller, Ralf P. Brandes^*

^*Corresponding author for this work

Luxembourg Center of Neuropathology

Research output: Contribution to journal › Article › Research › peer-review

182 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	65-79
Number of pages	15
Journal	Circulation
Volume	136
Issue number	1
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.116.026991
Publication status	Published - 4 Jul 2017

Keywords

RNA, long noncoding
epigenomics
glioblastoma
hypertension, pulmonary
neovascularization, physiologic

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10.1161/CIRCULATIONAHA.116.026991

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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., ... Brandes, R. P. (2017). Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function. Circulation, 136(1), 65-79. https://doi.org/10.1161/CIRCULATIONAHA.116.026991

@article{6eb747b891704b2e9c350290f48d512b,

title = "Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function",

abstract = "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.",

keywords = "RNA, long noncoding, epigenomics, glioblastoma, hypertension, pulmonary, neovascularization, physiologic",

author = "Leisegang, {Matthias S.} and Christian Fork and Ivana Josipovic and Richter, {Florian Martin} and Jens Preussner and Jiong Hu and Miller, {Matthew J.} and Jeremy Epah and Patrick Hofmann and Stefan G{\"u}nther and Franziska Moll and Chanil Valasarajan and Juliana Heidler and Yuliya Ponomareva and Freiman, {Thomas M.} and Lars Maegdefessel and Plate, {Karl H.} and Michel Mittelbronn and Shizuka Uchida and Carsten K{\"u}nne and Konstantinos Stellos and Schermuly, {Ralph T.} and Norbert Weissmann and Kavi Devraj and Ilka Wittig and Boon, {Reinier A.} and Stefanie Dimmeler and Pullamsetti, {Soni Savai} and Mario Looso and Miller, {Francis J.} and Brandes, {Ralf P.}",

note = "Publisher Copyright: {\textcopyright} 2017 American Heart Association, Inc.",

year = "2017",

month = jul,

day = "4",

doi = "10.1161/CIRCULATIONAHA.116.026991",

language = "English",

volume = "136",

pages = "65--79",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "1",

}

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 & Brandes, RP 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

TY - JOUR

T1 - Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function

AU - Leisegang, Matthias S.

AU - Fork, Christian

AU - Josipovic, Ivana

AU - Richter, Florian Martin

AU - Preussner, Jens

AU - Hu, Jiong

AU - Miller, Matthew J.

AU - Epah, Jeremy

AU - Hofmann, Patrick

AU - Günther, Stefan

AU - Moll, Franziska

AU - Valasarajan, Chanil

AU - Heidler, Juliana

AU - Ponomareva, Yuliya

AU - Freiman, Thomas M.

AU - Maegdefessel, Lars

AU - Plate, Karl H.

AU - Mittelbronn, Michel

AU - Uchida, Shizuka

AU - Künne, Carsten

AU - Stellos, Konstantinos

AU - Schermuly, Ralph T.

AU - Weissmann, Norbert

AU - Devraj, Kavi

AU - Wittig, Ilka

AU - Boon, Reinier A.

AU - Dimmeler, Stefanie

AU - Pullamsetti, Soni Savai

AU - Looso, Mario

AU - Miller, Francis J.

AU - Brandes, Ralf P.

PY - 2017/7/4

Y1 - 2017/7/4

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.

AB - 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

UR - http://www.scopus.com/inward/record.url?scp=85021717451&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.116.026991

DO - 10.1161/CIRCULATIONAHA.116.026991

M3 - Article

C2 - 28351900

AN - SCOPUS:85021717451

SN - 0009-7322

VL - 136

SP - 65

EP - 79

JO - Circulation

JF - Circulation

IS - 1

ER -

Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function

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Keywords

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