Exercise increases hyper-acetylation of histones on the Cis-element of NRF-1 binding to the Mef2a promoter: Implications on type 2 diabetes

Biochem Biophys Res Commun. 2017 Apr 22;486(1):83-87. doi: 10.1016/j.bbrc.2017.03.002. Epub 2017 Mar 2.

Abstract

Exercise brings changes on the chromatin ensuing the upregulation of many genes that confer protection from type 2 diabetes. In type-2 diabetes, critical genes are down-regulated such as those involved in glucose transport (GLUT4, MEF2A) and also oxidative phosphorylation (NRF-1 and its target genes). Recent reports have shown that NRF-1 not only regulate mitochondrial oxidative genes but also controls MEF2A, the main transcription factor for glucose transporter, GLUT4. Such dual control of the two pathways by NRF-1 place it as critical gene in the design of therapeutic modalities much needed to cure or better manage type 2 diabetes. Although it is known that NRF-1 controls these dual pathways (glucose transport and oxidative phosphorylation), the actual molecular mechanisms involved surrounding this regulation remains elusive. NRF-1 itself is regulated through posttranslational modifications (acetylation, methylation and phosphorylation) resulting in enhanced binding to its target genes. This study is therefore aimed at assessing whether CaMKII, a kinase activated by exercise brings about hyper-acetylation of histones in the vicinity of NRF-1 target gene, Mef2a. Five to six weeks old male Wistar rats were used in this study. Chromatin immunoprecipitation (ChIP) assay was used to investigate the extent through which NRF-1 is bound to the Mef2a gene and if this was associated with hyper-acetylation of histones in the region of NRF-1 binding site of the Mef2a gene. Quantitative real time PCR (qPCR) was used to determine the gene expression of MEF2A and NRF-1. Results from this study indicated that exercise-induced CaMKII activation increased hyper-acetylation of histones in the region of NRF-1 binding site on vicinity of Mef2a gene and this was associated with the increased binding of NRF-1 to Mef2a gene. Exercise also increased the expression of NRF-1 and MEF2A genes. Administration of CaMKII inhibitor (KN93) prior to exercise attenuated the observed exercise-induced increase of NRF-1 and MEF2A expressions. In conclusion, this study demonstrated for the first time in our knowledge one mechanism through which NRF-1 regulates MEF2A, pathway critical in glucose transport.

Keywords: CaMKII; Exercise; Hyper-acetylation; MEF2A; NRF-1; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Benzylamines / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Gene Expression / drug effects
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Histones / metabolism*
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • NF-E2-Related Factor 1 / genetics*
  • NF-E2-Related Factor 1 / metabolism
  • Physical Conditioning, Animal*
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology
  • Rats, Wistar
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology

Substances

  • Benzylamines
  • Glucose Transporter Type 4
  • Histones
  • MEF2 Transcription Factors
  • MEF2A protein, rat
  • NF-E2-Related Factor 1
  • Protein Kinase Inhibitors
  • Sulfonamides
  • KN 93
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2