LncRNA Meg3 protects endothelial function by regulating the DNA damage response

Mohamed Sham Shihabudeen Haider Ali, Xiao Cheng, Matthew Moran, Stefan Haemmig, Michael J. Naldrett, Sophie Alvarez, Mark W. Feinberg, Xinghui Sun

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis.

Original languageEnglish (US)
JournalNucleic Acids Research
Volume47
Issue number3
DOIs
StatePublished - Jan 1 2019

Fingerprint

Polypyrimidine Tract-Binding Protein
DNA Damage
p53 Genes
Endothelial Cells
Long Noncoding RNA
Genes
Cell Proliferation
Gene Silencing
Apoptosis
Gene Expression
RNA-Binding Proteins
Homeostasis

ASJC Scopus subject areas

  • Genetics

Cite this

Ali, M. S. S. H., Cheng, X., Moran, M., Haemmig, S., Naldrett, M. J., Alvarez, S., ... Sun, X. (2019). LncRNA Meg3 protects endothelial function by regulating the DNA damage response. Nucleic Acids Research, 47(3). https://doi.org/10.1093/nar/gky1190

LncRNA Meg3 protects endothelial function by regulating the DNA damage response. / Ali, Mohamed Sham Shihabudeen Haider; Cheng, Xiao; Moran, Matthew; Haemmig, Stefan; Naldrett, Michael J.; Alvarez, Sophie; Feinberg, Mark W.; Sun, Xinghui.

In: Nucleic Acids Research, Vol. 47, No. 3, 01.01.2019.

Research output: Contribution to journalArticle

Ali, MSSH, Cheng, X, Moran, M, Haemmig, S, Naldrett, MJ, Alvarez, S, Feinberg, MW & Sun, X 2019, 'LncRNA Meg3 protects endothelial function by regulating the DNA damage response', Nucleic Acids Research, vol. 47, no. 3. https://doi.org/10.1093/nar/gky1190
Ali MSSH, Cheng X, Moran M, Haemmig S, Naldrett MJ, Alvarez S et al. LncRNA Meg3 protects endothelial function by regulating the DNA damage response. Nucleic Acids Research. 2019 Jan 1;47(3). https://doi.org/10.1093/nar/gky1190
Ali, Mohamed Sham Shihabudeen Haider ; Cheng, Xiao ; Moran, Matthew ; Haemmig, Stefan ; Naldrett, Michael J. ; Alvarez, Sophie ; Feinberg, Mark W. ; Sun, Xinghui. / LncRNA Meg3 protects endothelial function by regulating the DNA damage response. In: Nucleic Acids Research. 2019 ; Vol. 47, No. 3.
@article{988cb3bf0e9247e59765f1f8a9009dd0,
title = "LncRNA Meg3 protects endothelial function by regulating the DNA damage response",
abstract = "The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis.",
author = "Ali, {Mohamed Sham Shihabudeen Haider} and Xiao Cheng and Matthew Moran and Stefan Haemmig and Naldrett, {Michael J.} and Sophie Alvarez and Feinberg, {Mark W.} and Xinghui Sun",
year = "2019",
month = "1",
day = "1",
doi = "10.1093/nar/gky1190",
language = "English (US)",
volume = "47",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - LncRNA Meg3 protects endothelial function by regulating the DNA damage response

AU - Ali, Mohamed Sham Shihabudeen Haider

AU - Cheng, Xiao

AU - Moran, Matthew

AU - Haemmig, Stefan

AU - Naldrett, Michael J.

AU - Alvarez, Sophie

AU - Feinberg, Mark W.

AU - Sun, Xinghui

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis.

AB - The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis.

UR - http://www.scopus.com/inward/record.url?scp=85062967453&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062967453&partnerID=8YFLogxK

U2 - 10.1093/nar/gky1190

DO - 10.1093/nar/gky1190

M3 - Article

VL - 47

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 3

ER -