MEF2 transcription factors are key regulators of sprouting angiogenesis

Research output: Contribution to journalArticlepeer-review

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MEF2 transcription factors are key regulators of sprouting angiogenesis. / Sacilotto, Natalia; Chouliaras, Kira M; Nikitenko, Leonid L; Lu, Yao Wei; Fritzsche, Martin; Wallace, Marsha D; Nornes, Svanhild; García-Moreno, Fernando; Payne, Sophie; Bridges, Esther; Liu, Ke; Biggs, Daniel; Ratnayaka, Indrika; Herbert, Shane P; Molnár, Zoltán; Harris, Adrian L; Davies, Benjamin; Bond, Gareth L; Bou-Gharios, George; Schwarz, John J; De Val, Sarah.

In: Genes & Development, Vol. 30, No. 20, 15.10.2016, p. 2297-2309.

Research output: Contribution to journalArticlepeer-review

Harvard

Sacilotto, N, Chouliaras, KM, Nikitenko, LL, Lu, YW, Fritzsche, M, Wallace, MD, Nornes, S, García-Moreno, F, Payne, S, Bridges, E, Liu, K, Biggs, D, Ratnayaka, I, Herbert, SP, Molnár, Z, Harris, AL, Davies, B, Bond, GL, Bou-Gharios, G, Schwarz, JJ & De Val, S 2016, 'MEF2 transcription factors are key regulators of sprouting angiogenesis', Genes & Development, vol. 30, no. 20, pp. 2297-2309. https://doi.org/10.1101/gad.290619.116

APA

Sacilotto, N., Chouliaras, K. M., Nikitenko, L. L., Lu, Y. W., Fritzsche, M., Wallace, M. D., Nornes, S., García-Moreno, F., Payne, S., Bridges, E., Liu, K., Biggs, D., Ratnayaka, I., Herbert, S. P., Molnár, Z., Harris, A. L., Davies, B., Bond, G. L., Bou-Gharios, G., ... De Val, S. (2016). MEF2 transcription factors are key regulators of sprouting angiogenesis. Genes & Development, 30(20), 2297-2309. https://doi.org/10.1101/gad.290619.116

Vancouver

Sacilotto N, Chouliaras KM, Nikitenko LL, Lu YW, Fritzsche M, Wallace MD et al. MEF2 transcription factors are key regulators of sprouting angiogenesis. Genes & Development. 2016 Oct 15;30(20):2297-2309. https://doi.org/10.1101/gad.290619.116

Author

Sacilotto, Natalia ; Chouliaras, Kira M ; Nikitenko, Leonid L ; Lu, Yao Wei ; Fritzsche, Martin ; Wallace, Marsha D ; Nornes, Svanhild ; García-Moreno, Fernando ; Payne, Sophie ; Bridges, Esther ; Liu, Ke ; Biggs, Daniel ; Ratnayaka, Indrika ; Herbert, Shane P ; Molnár, Zoltán ; Harris, Adrian L ; Davies, Benjamin ; Bond, Gareth L ; Bou-Gharios, George ; Schwarz, John J ; De Val, Sarah. / MEF2 transcription factors are key regulators of sprouting angiogenesis. In: Genes & Development. 2016 ; Vol. 30, No. 20. pp. 2297-2309.

Bibtex

@article{6a109506decc44bd9c6ee6df89c4cd90,
title = "MEF2 transcription factors are key regulators of sprouting angiogenesis",
abstract = "Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.",
keywords = "Animals, Cells, Cultured, Embryo, Nonmammalian, Endothelial Cells/cytology, Enhancer Elements, Genetic/genetics, Gene Expression Regulation, Developmental, Histone Deacetylases/genetics, Humans, Intracellular Signaling Peptides and Proteins/genetics, MEF2 Transcription Factors/chemistry, Membrane Proteins/genetics, Mice, Neovascularization, Pathologic/genetics, Neovascularization, Physiologic/genetics, Protein Interaction Domains and Motifs, Retina/embryology, Signal Transduction, Vascular Endothelial Growth Factor A/metabolism, Zebrafish",
author = "Natalia Sacilotto and Chouliaras, {Kira M} and Nikitenko, {Leonid L} and Lu, {Yao Wei} and Martin Fritzsche and Wallace, {Marsha D} and Svanhild Nornes and Fernando Garc{\'i}a-Moreno and Sophie Payne and Esther Bridges and Ke Liu and Daniel Biggs and Indrika Ratnayaka and Herbert, {Shane P} and Zolt{\'a}n Moln{\'a}r and Harris, {Adrian L} and Benjamin Davies and Bond, {Gareth L} and George Bou-Gharios and Schwarz, {John J} and {De Val}, Sarah",
note = "{\textcopyright} 2016 Sacilotto et al.; Published by Cold Spring Harbor Laboratory Press.",
year = "2016",
month = oct,
day = "15",
doi = "10.1101/gad.290619.116",
language = "English",
volume = "30",
pages = "2297--2309",
journal = "Genes & Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "20",

}

RIS

TY - JOUR

T1 - MEF2 transcription factors are key regulators of sprouting angiogenesis

AU - Sacilotto, Natalia

AU - Chouliaras, Kira M

AU - Nikitenko, Leonid L

AU - Lu, Yao Wei

AU - Fritzsche, Martin

AU - Wallace, Marsha D

AU - Nornes, Svanhild

AU - García-Moreno, Fernando

AU - Payne, Sophie

AU - Bridges, Esther

AU - Liu, Ke

AU - Biggs, Daniel

AU - Ratnayaka, Indrika

AU - Herbert, Shane P

AU - Molnár, Zoltán

AU - Harris, Adrian L

AU - Davies, Benjamin

AU - Bond, Gareth L

AU - Bou-Gharios, George

AU - Schwarz, John J

AU - De Val, Sarah

N1 - © 2016 Sacilotto et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2016/10/15

Y1 - 2016/10/15

N2 - Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.

AB - Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.

KW - Animals

KW - Cells, Cultured

KW - Embryo, Nonmammalian

KW - Endothelial Cells/cytology

KW - Enhancer Elements, Genetic/genetics

KW - Gene Expression Regulation, Developmental

KW - Histone Deacetylases/genetics

KW - Humans

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - MEF2 Transcription Factors/chemistry

KW - Membrane Proteins/genetics

KW - Mice

KW - Neovascularization, Pathologic/genetics

KW - Neovascularization, Physiologic/genetics

KW - Protein Interaction Domains and Motifs

KW - Retina/embryology

KW - Signal Transduction

KW - Vascular Endothelial Growth Factor A/metabolism

KW - Zebrafish

U2 - 10.1101/gad.290619.116

DO - 10.1101/gad.290619.116

M3 - Article

C2 - 27898394

VL - 30

SP - 2297

EP - 2309

JO - Genes & Development

JF - Genes & Development

SN - 0890-9369

IS - 20

ER -