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.
journal_name
Proc Natl Acad Sci U S Aauthors
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 A,Zhou Jdoi
10.1073/pnas.1803725115subject
Has Abstractpub_date
2018-09-11 00:00:00pages
E8660-E8667issue
37eissn
0027-8424issn
1091-6490pii
1803725115journal_volume
115pub_type
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