Abstract
In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) NEAT1 is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of NEAT1 in VSMC phenotypic modulation is unknown. Herein we showed that NEAT1 expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing NEAT1 in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of NEAT1 in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which NEAT1 knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that NEAT1 sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic “off” state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA NEAT1 in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that NEAT1 is a therapeutic target for treating occlusive vascular diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | E8660-E8667 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 37 |
| DOIs | |
| State | Published - Sep 11 2018 |
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Keywords
- Epigenetic regulation
- Gene expression
- Long noncoding RNA
- Phenotypic switching
- Smooth muscle cells
ASJC Scopus subject areas
- General
Cite this
Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells. / Ahmed, Abu Shufian Ishtiaq; Dong, Kunzhe; Liu, Jinhua; Wen, Tong; Yu, Luyi; Xu, Fei; Kang, Xiuhua; Osman, Islam; Hu, Guoqing; Bunting, Kristopher M.; Crethers, Danielle; Gao, Hongyu; Zhang, Wei; Liu, Yunlong; Wen, Ke; Agarwal, Gautam; Hirose, Tetsuro; Nakagawa, Shinichi; Vazdarjanova, Almira Ivanova; Zhou, Jiliang.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 37, 11.09.2018, p. E8660-E8667.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells
AU - Ahmed, Abu Shufian Ishtiaq
AU - Dong, Kunzhe
AU - Liu, Jinhua
AU - Wen, Tong
AU - Yu, Luyi
AU - Xu, Fei
AU - Kang, Xiuhua
AU - Osman, Islam
AU - Hu, Guoqing
AU - Bunting, Kristopher M.
AU - Crethers, Danielle
AU - Gao, Hongyu
AU - Zhang, Wei
AU - Liu, Yunlong
AU - Wen, Ke
AU - Agarwal, Gautam
AU - Hirose, Tetsuro
AU - Nakagawa, Shinichi
AU - Vazdarjanova, Almira Ivanova
AU - Zhou, Jiliang
PY - 2018/9/11
Y1 - 2018/9/11
N2 - In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) NEAT1 is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of NEAT1 in VSMC phenotypic modulation is unknown. Herein we showed that NEAT1 expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing NEAT1 in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of NEAT1 in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which NEAT1 knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that NEAT1 sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic “off” state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA NEAT1 in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that NEAT1 is a therapeutic target for treating occlusive vascular diseases.
AB - In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) NEAT1 is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of NEAT1 in VSMC phenotypic modulation is unknown. Herein we showed that NEAT1 expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing NEAT1 in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of NEAT1 in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which NEAT1 knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that NEAT1 sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic “off” state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA NEAT1 in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that NEAT1 is a therapeutic target for treating occlusive vascular diseases.
KW - Epigenetic regulation
KW - Gene expression
KW - Long noncoding RNA
KW - Phenotypic switching
KW - Smooth muscle cells
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U2 - 10.1073/pnas.1803725115
DO - 10.1073/pnas.1803725115
M3 - Article
VL - 115
SP - E8660-E8667
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 37
ER -