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HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis

Author

Listed:
  • TingDong Yan

    (Duke-NUS Medical School)

  • Wen Fong Ooi

    (Genome Institute of Singapore)

  • Aditi Qamra

    (Genome Institute of Singapore
    National University of Singapore)

  • Alice Cheung

    (Duke-NUS Medical School)

  • DongLiang Ma

    (Duke-NUS Medical School
    National Neuroscience Institute)

  • Gopinath Meenakshi Sundaram

    (Institute of Medical Biology (IMB))

  • Chang Xu

    (Duke-NUS Medical School
    National University of Singapore)

  • Manjie Xing

    (Duke-NUS Medical School
    Genome Institute of Singapore)

  • LaiFong Poon

    (Duke-NUS Medical School)

  • Jing Wang

    (Duke-NUS Medical School)

  • Yan Ping Loh

    (National University of Singapore
    Nanyang Technological University)

  • Jess Hui Jie Ho

    (Duke-NUS Medical School)

  • Joscelyn Jun Quan Ng

    (Duke-NUS Medical School)

  • Muhammad Khairul Ramlee

    (Duke-NUS Medical School)

  • Luay Aswad

    (National University of Singapore
    Nanyang Technological University)

  • Steve G. Rozen

    (Duke-NUS Medical School
    Duke-NUS Medical School)

  • Sujoy Ghosh

    (Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School)

  • Frederic A. Bard

    (Institute of Molecular and Cell Biology (IMCB))

  • Prabha Sampath

    (Duke-NUS Medical School
    Institute of Medical Biology (IMB))

  • Vinay Tergaonkar

    (Institute of Molecular and Cell Biology (IMCB))

  • James O. J. Davies

    (Oxford University)

  • Jim R. Hughes

    (Oxford University)

  • Eyleen Goh

    (National University of Singapore
    Duke-NUS Medical School
    National Neuroscience Institute)

  • Xuezhi Bi

    (Bioprocessing Technology Institute)

  • Melissa Jane Fullwood

    (National University of Singapore
    Nanyang Technological University
    Institute of Molecular and Cell Biology (IMCB))

  • Patrick Tan

    (Duke-NUS Medical School
    National University of Singapore
    National University of Singapore
    Duke-NUS Medical School)

  • Shang Li

    (Duke-NUS Medical School
    National University of Singapore)

Abstract

The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain largely unclear. Here we describe how miR-615-3p represses hTERT expression. mir-615-3p is located in an intron of the HOXC5 gene, a member of the highly conserved homeobox family of transcription factors controlling embryogenesis and development. Unexpectedly, we found that HoxC5 also represses hTERT expression by disrupting the long-range interaction between hTERT promoter and its distal enhancer. The 3′UTR of hTERT and its upstream enhancer region are well conserved in long-lived primates. Both mir-615-3p and HOXC5 are activated upon differentiation, which constitute a feed-forward loop that coordinates transcriptional and post-transcriptional repression of hTERT during cellular differentiation. Deregulation of HOXC5 and mir-615-3p expression may contribute to the activation of hTERT in human cancers.

Suggested Citation

  • TingDong Yan & Wen Fong Ooi & Aditi Qamra & Alice Cheung & DongLiang Ma & Gopinath Meenakshi Sundaram & Chang Xu & Manjie Xing & LaiFong Poon & Jing Wang & Yan Ping Loh & Jess Hui Jie Ho & Joscelyn Ju, 2018. "HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02601-1
    DOI: 10.1038/s41467-017-02601-1
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