Genome-scale network model of metabolism and histone acetylation reveals metabolic dependencies of histone deacetylase inhibitors

Genome Biol. 2019 Mar 1;20(1):49. doi: 10.1186/s13059-019-1661-z.

Abstract

Histone acetylation plays a central role in gene regulation and is sensitive to the levels of metabolic intermediates. However, predicting the impact of metabolic alterations on acetylation in pathological conditions is a significant challenge. Here, we present a genome-scale network model that predicts the impact of nutritional environment and genetic alterations on histone acetylation. It identifies cell types that are sensitive to histone deacetylase inhibitors based on their metabolic state, and we validate metabolites that alter drug sensitivity. Our model provides a mechanistic framework for predicting how metabolic perturbations contribute to epigenetic changes and sensitivity to deacetylase inhibitors.

Keywords: Genome-scale metabolic modeling; KDAC inhibitors; Metabolic network; Metabolic regulation; Protein acetylation; Protein deacetylases (KDACs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • HeLa Cells
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / metabolism*
  • Humans
  • Metabolism*
  • Models, Genetic*
  • Vorinostat / pharmacology*

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Vorinostat