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Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation

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  • Jun Guo

    (National Center of Gerontology)

  • Weiwei Fang

    (National Center of Gerontology
    Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Libo Sun

    (Capital Medical University)

  • Yonggang Lu

    (National Center of Gerontology)

  • Lin Dou

    (National Center of Gerontology)

  • Xiuqing Huang

    (National Center of Gerontology)

  • Weiqing Tang

    (National Center of Gerontology
    Georgia State University)

  • Liqing Yu

    (Georgia State University)

  • Jian Li

    (National Center of Gerontology
    Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences)

Abstract

Ultraconserved (uc) RNAs, a class of long non-coding RNAs (lncRNAs), are conserved across humans, mice, and rats, but the physiological significance and pathological role of ucRNAs is largely unknown. Here we show that uc.372 is upregulated in the livers of db/db mice, HFD-fed mice, and NAFLD patients. Gain-of-function and loss-of-function studies indicate that uc.372 drives hepatic lipid accumulation in mice by promoting lipogenesis. We further demonstrate that uc.372 binds to pri-miR-195/pri-miR-4668 and suppresses maturation of miR-195/miR-4668 to regulate expression of genes related to lipid synthesis and uptake, including ACC, FAS, SCD1, and CD36. Finally, we identify that uc.372 is located downstream of the insulinoma-associated 2 (INSM2) gene that is transcriptionally activated by upstream transcription factor 1 (USF1). Our findings reveal a novel mechanism by which uc.372 drives hepatic steatosis through inhibition of miR-195/miR-4668 maturation to relieve miR-195/miR-4668-mediated suppression of functional target gene expression.

Suggested Citation

  • Jun Guo & Weiwei Fang & Libo Sun & Yonggang Lu & Lin Dou & Xiuqing Huang & Weiqing Tang & Liqing Yu & Jian Li, 2018. "Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03072-8
    DOI: 10.1038/s41467-018-03072-8
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