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Chemical genomics reveals histone deacetylases are required for core regulatory transcription

  1. Author:
    Gryder, Berkley E.
    Wu, Lei
    Woldemichael,Girma
    Pomella, Silvia
    Quinn, Taylor R.
    Park, Paul M. C.
    Cleveland, Abigail
    Stanton, Benjamin Z.
    Song, Young
    Rota, Rossella
    Wiest, Olaf
    Yohe, Marielle E.
    Shern, Jack F.
    Qi, Jun
    Khan, Javed

  2. Author Address

    NCI, Genet Branch, NIH, Bethesda, MD 20892 USA.Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.Frederick Natl Lab Canc Res, Mol Targets Lab, Frederick, MD 21701 USA.Osped Pediat Bambino Gesu Res Inst, Dept Oncohematol, Lab Angiogenesis, I-00165 Rome, Italy.Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA.NCI, Pediat Oncol Branch, CCR, NIH, Bethesda, MD 20814 USA.Harvard Med Sch, Dept Med, Boston, MA 02115 USA.
    1. Year: 2019
    2. Date: Jul 8
    3. Epub Date: 2019 07 08
  2. Journal: Nature communications
  3. NATURE PUBLISHING GROUP,
    1. 10
    2. 1
  5. Type of Article: Article
  6. Article Number: 3004
  7. ISSN: 2041-1723
  1. Abstract:

    Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.

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External Sources

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  2. DOI: 10.1038/s41467-019-11046-7
  3. PMID: 31285436
  4. PMCID: PMC6614369
  5. View record in Web of Science®
  6. WOS: 000474336500001

Library Notes

  1. Fiscal Year: FY2018-2019
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