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Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2019 May; Vol. 15 (5), pp. 519-528. Date of Electronic Publication: 2019 Apr 08. - Publication Year :
- 2019
-
Abstract
- Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.
- Subjects :
- Benzimidazoles chemistry
CREB-Binding Protein genetics
CREB-Binding Protein metabolism
E1A-Associated p300 Protein genetics
E1A-Associated p300 Protein metabolism
Enzyme Inhibitors chemistry
Fibroblasts cytology
Fibroblasts metabolism
Humans
Isoxazoles chemistry
Molecular Structure
Oxazepines chemistry
Piperidines chemistry
Protein Domains drug effects
Benzimidazoles pharmacology
CREB-Binding Protein antagonists & inhibitors
Cellular Reprogramming drug effects
E1A-Associated p300 Protein antagonists & inhibitors
Enzyme Inhibitors pharmacology
Fibroblasts drug effects
Isoxazoles pharmacology
Oxazepines pharmacology
Piperidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 15
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 30962627
- Full Text :
- https://doi.org/10.1038/s41589-019-0264-z