Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells

Abu Shufian Ishtiaq Ahmed, Kunzhe Dong, Jinhua Liu, Tong Wen, Luyi Yu, Fei Xu, Xiuhua Kang, Islam Osman, Guoqing Hu, Kristopher M. Bunting, Danielle Crethers, Hongyu Gao, Wei Zhang, Yunlong Liu, Ke Wen, Gautam Agarwal, Tetsuro Hirose, Shinichi Nakagawa, Almira Ivanova Vazdarjanova, Jiliang Zhou

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)E8660-E8667
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number37
DOIs
StatePublished - Sep 11 2018

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Long Noncoding RNA
Vascular Smooth Muscle
Smooth Muscle Myocytes
Neointima
Vascular System Injuries
Cell Proliferation
Epigenomics
Cell Movement
Gene Expression
Vascular Diseases
Knockout Mice
Genes
Chromatin
Carcinogenesis
Down-Regulation
Phenotype

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 journalArticle

Ahmed, ASI, Dong, K, Liu, J, Wen, T, Yu, L, Xu, F, Kang, X, Osman, I, Hu, G, Bunting, KM, Crethers, D, Gao, H, Zhang, W, Liu, Y, Wen, K, Agarwal, G, Hirose, T, Nakagawa, S, Vazdarjanova, AI & Zhou, J 2018, 'Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 37, pp. E8660-E8667. https://doi.org/10.1073/pnas.1803725115
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. / Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 37. pp. E8660-E8667.
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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.",
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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.

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KW - Gene expression

KW - Long noncoding RNA

KW - Phenotypic switching

KW - Smooth muscle cells

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JF - Proceedings of the National Academy of Sciences of the United States of America

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