期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 37, 页码 E8660-E8667出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1803725115
关键词
long noncoding RNA; smooth muscle cells; phenotypic switching; gene expression; epigenetic regulation
资金
- National Cancer Institute Cancer Center Support Grant [P30 CA91842]
- Washington University Institute of Clinical and Translational Sciences (ICTS)/Clinical and Translational Science Award (CTSA) Grant from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1TR000448]
- NIH Roadmap for Medical Research
- National Heart, Lung, and Blood Institute, NIH
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 (IncRNA) 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 IncRNA 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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