title: Exercise increases hyper-acetylation of histones on the Cis-element of NRF-1 binding to the Mef2a promoter: Implications on type 2 diabetes.
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.
authors.affiliation: Department of Biochemistry, University of Johannesburg, Auckland Park 2006, South Africa.
authors.forename: Jitcy S
authors.initials: JS
authors.lastname: Joseph
authors.affiliation: Department of Biological Sciences, North-West University, Mafikeng Campus, Mmabatho 2735, South Africa.
authors.forename: Ademola O
authors.initials: AO
authors.lastname: Ayeleso
authors.affiliation: Department of Biological Sciences, North-West University, Mafikeng Campus, Mmabatho 2735, South Africa. Electronic address: Emmanuel.Mukwevho@nwu.ac.za.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mukwevho
mesh_terms: D000107:Acetylation; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051265:NF-E2-Related Factor 1 / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017208:Rats, Wistar; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051275:Glucose Transporter Type 4; D006657:Histones; D064326:MEF2 Transcription Factors; D051265:NF-E2-Related Factor 1; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C578037:MEF2A protein, rat; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: CaMKII; Exercise; Hyper-acetylation; MEF2A; NRF-1; Type 2 diabetes