Browsing by Subject "Long noncoding RNA"

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    Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells
    (National Academy of Sciences, 2018-09-11) 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; Zhou, Jiliang; Medicine, School of Medicine
    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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    MIR193BHG: a novel hypoxia-inducible long noncoding RNA involved in the fine-tuning of cholesterol metabolism
    (2016-09-22) Wu, Xue; Ivan, Mircea; Radovich, Milan; Srour, Edward F.; Yu, Andy Qigui
    The human genome generates a vast number of functionally and structurally diverse noncoding transcripts, incorporated into complex networks which modulate the activity of classic pathways. Long noncoding RNAs (lncRNA) have been shown to exhibit diverse regulatory roles in various physiological and pathological processes. Hypoxia, a key feature of the tumor microenvironment, triggers adaptive responses in cancer cells that involve hundreds of genes. While the coding component of hypoxia signaling has been extensively studied, much less information is available regarding its noncoding arm. My doctoral work identified and functionally characterized a novel hypoxia-inducible lncRNAs encoded from the miR193b-host gene (MIR193BHG) locus, on chromosome 16. In the pursuit of understanding how MIR193BHG responds to hypoxia, we discovered a more complex transcriptional control of MIR193BHG by hypoxia. Ectopic expression of MIR193BHG in breast cancer cell lines in vitro and in xenografts significantly represses cell invasion, as well as the metastasis to lung and liver. Conversely, inhibition of MIR193BHG promotes cancer cell invasiveness and metastasis. RNAseq followed by pathway analysis revealed that MIR193BHG is a negative modulator of cholesterol biosynthesis pathway. MIR193BHG exerts a highly coordinated effect on the expression of cholesterol biosynthetic genes which leads to a measurable impact on the total cellular cholesterol content. The role of MIR193BHG in cholesterol metabolism also provided a mechanistic explanation for the sex maturation associated SNPs located in vicinity of this gene locus. Our work also provided preliminary insights into the functional mechanism of MIR193BHG by showing that its modulation of genes in cholesterol synthesis is predominantly at transcriptional level. Overall, my dissertation project identified a non-canonical hypoxia-inducible lncRNA, MIR193BHG, which modulates breast cancer invasion and metastasis via finetuning of cholesterol synthesis.