Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes
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 ne...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-11-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2017.1371892 |
| _version_ | 1827811543018897408 |
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| author | Haloom Rafehi Antony Kaspi Mark Ziemann Jun Okabe Tom C. Karagiannis Assam El-Osta |
| author_facet | Haloom Rafehi Antony Kaspi Mark Ziemann Jun Okabe Tom C. Karagiannis Assam El-Osta |
| author_sort | Haloom Rafehi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:07:22Z |
| format | Article |
| id | doaj.art-5134259e194f440cb27c30eff0d0e99c |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:07:22Z |
| publishDate | 2017-11-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-5134259e194f440cb27c30eff0d0e99c2023-09-21T13:09:20ZengTaylor & Francis GroupEpigenetics1559-22941559-23082017-11-011211991100310.1080/15592294.2017.13718921371892Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetesHaloom Rafehi0Antony Kaspi1Mark Ziemann2Jun Okabe3Tom C. Karagiannis4Assam El-Osta5Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Monash UniversityGiven 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.http://dx.doi.org/10.1080/15592294.2017.1371892epigenomicshdac inhibitorsmeta-analysissahahistone acetylationdiabetesendothelial dysfunctionnetwork analysispathway analysiscomputation biology |
| spellingShingle | Haloom Rafehi Antony Kaspi Mark Ziemann Jun Okabe Tom C. Karagiannis Assam El-Osta Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes Epigenetics epigenomics hdac inhibitors meta-analysis saha histone acetylation diabetes endothelial dysfunction network analysis pathway analysis computation biology |
| title | Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes |
| title_full | Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes |
| title_fullStr | Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes |
| title_full_unstemmed | Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes |
| title_short | Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes |
| title_sort | systems approach to the pharmacological actions of hdac inhibitors reveals ep300 activities and convergent mechanisms of regulation in diabetes |
| topic | epigenomics hdac inhibitors meta-analysis saha histone acetylation diabetes endothelial dysfunction network analysis pathway analysis computation biology |
| url | http://dx.doi.org/10.1080/15592294.2017.1371892 |
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