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 Vazdarjanova, Jiliang Zhou

Research output: Contribution to journalArticle

33 Scopus citations

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

Keywords

  • Epigenetic regulation
  • Gene expression
  • Long noncoding RNA
  • Phenotypic switching
  • Smooth muscle cells

ASJC Scopus subject areas

  • General

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    Ahmed, A. S. I., Dong, K., Liu, J., Wen, T., Yu, L., Xu, F., Kang, X., Osman, I., Hu, G., Bunting, K. M., Crethers, D., Gao, H., Zhang, W., Liu, Y., Wen, K., Agarwal, G., Hirose, T., Nakagawa, S., Vazdarjanova, A., & 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, 115(37), E8660-E8667. https://doi.org/10.1073/pnas.1803725115