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SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

Author

Listed:
  • Ken Tajima

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Toshifumi Yae

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Sarah Javaid

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Oliver Tam

    (Cold Spring Harbor Laboratory)

  • Valentine Comaills

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Robert Morris

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Ben S. Wittner

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Mingzhu Liu

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Amanda Engstrom

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Fumiyuki Takahashi

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Joshua C. Black

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Sridhar Ramaswamy

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Toshihiro Shioda

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Molly Hammell

    (Cold Spring Harbor Laboratory)

  • Daniel A. Haber

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Johnathan R. Whetstine

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Shyamala Maheswaran

    (Massachusetts General Hospital Cancer Center, Harvard Medical School
    Harvard Medical School)

Abstract

Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.

Suggested Citation

  • Ken Tajima & Toshifumi Yae & Sarah Javaid & Oliver Tam & Valentine Comaills & Robert Morris & Ben S. Wittner & Mingzhu Liu & Amanda Engstrom & Fumiyuki Takahashi & Joshua C. Black & Sridhar Ramaswamy , 2015. "SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9257
    DOI: 10.1038/ncomms9257
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