Epigenetic regulation of PGC-1a expression in the liver of offspring subjected to antenatal exposure to glucocorticoids

Abstract

PGC-1a (Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha) is an efficient regulator of the energy metabolism. This transcription co-activator stimulates the mitochondrial biogenesis in skeletal muscle, thermogenesis in brown adipose tissue and the expression of gluconeogenesis enzymes in the liver. The multiple actions of PGC-1a are warranted by its ability to bind to several transcription factors such as PPAR (Peroxisome Proliferator-Activated Receptor) a e b, ERRa (Estrogen Receptor-Related a), FoxO1 (Forkhead Box O1), HNF4a (Hepatocyte Nuclear Factor 4a) and NRF1 (Nuclear Respiratory Factor 1). In terms of regulation, the gene that encodes PGC-1a - PPARGC1- is transcriptionally repressed by DNMT3-induced methylation of its promoter. In spite of this molecular characterization, whether a transcriptional regulation of PPARGC1 plays a role in metabolic programming is still uncertain. Unpublished data from our laboratory show that rats born to dexamethasone (DEX)-treated mothers are unable to increase the hepatic levels of gluconeogenesis enzymes and PGC-1a during a prolonged fasting. Aims: This project aims to analyze the methylation pattern of the PGC-1a promoter in the liver of rats born to DEX-treated mothers. The expression of DNA methyl-transferases (DNMT1, 3A e 3B) will be also assessed. Methods: Wistar rats born to rats treated with DEX during the last week of pregnancy (DEX group) will be killed at 1st, the 21st and the 90th days of life. A separate group of pregnant rats will be left untreated (control group). Fragments of liver will be used for qPCR and western blot detection of DNMT1, 3A and 3B and PGC-1a. DNA methylation will be performed by sample enrichment with protein-bound methylated fragments. After purification, the promoter fragments will be identified by qPCR. (AU)