Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes.
Haloom Rafehi, Antony Kaspi, Mark Ziemann, Jun Okabe, Tom C Karagiannis, Assam El-Osta
Author Information
Haloom Rafehi: a Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash University , Melbourne , Victoria , Australia.
Antony Kaspi: a Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash University , Melbourne , Victoria , Australia.
Mark Ziemann: a Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash University , Melbourne , Victoria , Australia.
Jun Okabe: a Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash University , Melbourne , Victoria , Australia.
Tom C Karagiannis: a Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash University , Melbourne , Victoria , Australia.
Assam El-Osta: a Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash University , Melbourne , Victoria , Australia.
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.
