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Nat Commun. 2019 Jul 8;10(1):3004. doi: 10.1038/s41467-019-11046-7.

Chemical genomics reveals histone deacetylases are required for core regulatory transcription.

Author information

1
Genetics Branch, NCI, NIH, Bethesda, MD, 20892, USA.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
3
Molecular Targets Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.
4
Department of Oncohematology, Laboratory of Angiogenesis, Ospedale Pediatrico Bambino Gesu' Research Institute, Rome, 00165, Italy.
5
Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
6
Pediatric Oncology Branch, CCR, NCI, NIH, Bethesda, MD, 20814, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. jun_qi@dfci.harvard.edu.
8
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. jun_qi@dfci.harvard.edu.
9
Genetics Branch, NCI, NIH, Bethesda, MD, 20892, USA. khanjav@mail.nih.gov.

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.

PMID:
31285436
PMCID:
PMC6614369
DOI:
10.1038/s41467-019-11046-7
[Indexed for MEDLINE]
Free PMC Article

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