Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring.
We examined transcriptional and epigenetic mechanism(s) behind diminished skeletal muscle GLUT4 mRNA in intrauterine growth-restricted (IUGR) female rat offspring. An increase in MEF2D (inhibitor) with a decline in MEF2A (activator) and MyoD (co-activator) binding to the glut4 promoter in IUGR versus control was observed. The functional role of MEF2/MyoD-binding sites and neighboring three CpG clusters in glut4 gene transcription was confirmed in C2C12 muscle cells. No differential methylation of these three and other CpG clusters in the glut4 promoter occurred. DNA methyltransferase 1 (DNMT1) in postnatal, DNMT3a, and DNMT3b in adult was differentially recruited with increased MeCP2 (methyl CpG-binding protein) concentrations to bind the IUGR glut4 gene. Covalent modifications of the histone (H) code consisted of H3.K14 de-acetylation by recruitment of histone deacetylase (HDAC) 1 and enhanced association of HDAC4 enzymes. This set the stage for Suv39H1 methylase-mediated di-methylation of H3.K9 and increased recruitment of heterochromatin protein 1alpha, which partially inactivates postnatal and adult IUGR glut4 gene transcription. Further increased interactions in the adult IUGR between DNMT3a/DNMT3b and HDAC1 and MEF2D and HDAC1/HDAC4 and decreased association between MyoD and MEF2A existed. We conclude that epigenetic mechanisms consisting of histone code modifications repress skeletal muscle glut4 transcription in the postnatal period and persist in the adult female IUGR offspring.
Raychaudhuri
Nupur
N
Division of Neonatology and Developmental Biology and the Neonatal Research Center, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1752, USA.
Raychaudhuri
Santanu
S
Thamotharan
Manikkavasagar
M
Devaskar
Sherin U
SU
D000818:Animals; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism*; D042421:Histone Code; D006657:Histones / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D051275:Glucose Transporter Type 4; D006657:Histones; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C000619382:Dnmt1 protein, rat