Chemical genomics reveals histone deacetylases are required for core regulatory transcription.
Acetylation
/ drug effects
Cell Line, Tumor
Chromatin
/ drug effects
Enhancer Elements, Genetic
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Genomics
/ methods
High-Throughput Nucleotide Sequencing
High-Throughput Screening Assays
Histone Deacetylase Inhibitors
/ chemistry
Histone Deacetylases
/ chemistry
Humans
Molecular Dynamics Simulation
Molecular Probes
/ chemistry
Oncogene Proteins, Fusion
/ genetics
Paired Box Transcription Factors
/ genetics
Primary Cell Culture
Protein Isoforms
/ antagonists & inhibitors
Rhabdomyosarcoma
/ genetics
Sequence Analysis, RNA
Transcription, Genetic
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 07 2019
08 07 2019
Historique:
received:
05
11
2018
accepted:
28
05
2019
entrez:
10
7
2019
pubmed:
10
7
2019
medline:
11
10
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31285436
doi: 10.1038/s41467-019-11046-7
pii: 10.1038/s41467-019-11046-7
pmc: PMC6614369
doi:
Substances chimiques
Chromatin
0
Histone Deacetylase Inhibitors
0
Molecular Probes
0
Oncogene Proteins, Fusion
0
PAX3-FOXO1A fusion protein, human
0
Paired Box Transcription Factors
0
Protein Isoforms
0
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3004Subventions
Organisme : NCI NIH HHS
ID : P01 CA066996
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA142106
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P01-CA066996
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P01-CA142106
Pays : International
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