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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)991-1003
Number of pages13
JournalEpigenetics
Volume12
Issue number11
DOIs
Publication statusPublished - 2 Nov 2017

Keywords

  • computation biology
  • diabetes
  • endothelial dysfunction
  • epigenomics
  • HDAC inhibitors
  • histone acetylation
  • meta-analysis
  • network analysis
  • pathway analysis
  • SAHA

Cite this

@article{4d3b2c5b169b4ed5ae6132d498ebf67a,
title = "Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes",
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.",
keywords = "computation biology, diabetes, endothelial dysfunction, epigenomics, HDAC inhibitors, histone acetylation, meta-analysis, network analysis, pathway analysis, SAHA",
author = "Haloom Rafehi and Antony Kaspi and Mark Ziemann and Jun Okabe and Karagiannis, {Tom C.} and Assam El-Osta",
year = "2017",
month = "11",
day = "2",
doi = "10.1080/15592294.2017.1371892",
language = "English",
volume = "12",
pages = "991--1003",
journal = "Epigenetics",
issn = "1559-2294",
publisher = "Taylor & Francis",
number = "11",

}

Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes. / Rafehi, Haloom; Kaspi, Antony; Ziemann, Mark; Okabe, Jun; Karagiannis, Tom C.; El-Osta, Assam.

In: Epigenetics, Vol. 12, No. 11, 02.11.2017, p. 991-1003.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes

AU - Rafehi, Haloom

AU - Kaspi, Antony

AU - Ziemann, Mark

AU - Okabe, Jun

AU - Karagiannis, Tom C.

AU - El-Osta, Assam

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

AB - 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.

KW - computation biology

KW - diabetes

KW - endothelial dysfunction

KW - epigenomics

KW - HDAC inhibitors

KW - histone acetylation

KW - meta-analysis

KW - network analysis

KW - pathway analysis

KW - SAHA

UR - http://www.scopus.com/inward/record.url?scp=85038948312&partnerID=8YFLogxK

U2 - 10.1080/15592294.2017.1371892

DO - 10.1080/15592294.2017.1371892

M3 - Article

VL - 12

SP - 991

EP - 1003

JO - Epigenetics

JF - Epigenetics

SN - 1559-2294

IS - 11

ER -