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Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes
- Source :
- Epigenetics. 12(11)
- Publication Year :
- 2017
-
Abstract
- Given the skyrocketing costs to develop new drugs, repositioning of approved drugs, such as histone deacetylase (HDAC) inhibitors, may be a promising strategy to develop novel therapies. However, a gap exists in the understanding and advancement of these agents to meaningful translation for which new indications may emerge. To address this, we performed systems-level analyses of 33 independent HDAC inhibitor microarray studies. Based on network analysis, we identified enrichment for pathways implicated in metabolic syndrome and diabetes (insulin receptor signaling, lipid metabolism, immunity and trafficking). Integration with ENCODE ChIP-seq datasets identified suppression of EP300 target genes implicated in diabetes. Experimental validation indicates reversal of diabetes-associated EP300 target genes in primary vascular endothelial cells derived from a diabetic individual following inhibition of HDACs (by SAHA), EP300, or EP300 knockdown. Our computational systems biology approach provides an adaptable framework for the prediction of novel therapeutics for existing disease.
- Subjects :
- 0301 basic medicine
Cancer Research
Systems biology
Gene regulatory network
Biology
Bioinformatics
Epigenesis, Genetic
03 medical and health sciences
Diabetes Mellitus
Histone code
Humans
Gene Regulatory Networks
Molecular Biology
Cells, Cultured
Epigenesis
Epigenomics
Gene knockdown
Systems Biology
Endothelial Cells
Histone Code
Histone Deacetylase Inhibitors
Insulin receptor
030104 developmental biology
biology.protein
Histone deacetylase
Endothelium, Vascular
E1A-Associated p300 Protein
Research Paper
Subjects
Details
- ISSN :
- 15592308
- Volume :
- 12
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Epigenetics
- Accession number :
- edsair.doi.dedup.....56051836dbf89d08136920401ac77a5a