title: PPARα activation drives demethylation of the CpG islands of the Gadd45b promoter in the mouse liver.
abstract: Growth arrest and DNA damage-inducible beta (GADD45b) plays a pivotal role in many intracellular events in both cell survival- and cell death-related signaling. To date, the study of GADD35b has mainly focused on investigation of its function, as well as interacting molecules. However, studies of Gadd45b gene regulation are limited. In this study, we investigated the transcriptional regulation mechanism of Gadd45b. Since Gadd45b mRNA is highly induced by the PPARα agonist Wy-14,643 in the mouse liver, we analyzed the Gadd45b promoter using an in vivo reporter assay. Interestingly, the naked Gadd45b-luciferase construct strongly induced luciferase activity without any stimulant in our in vivo system. Therefore, we investigated the epigenetic changes in the Gadd45b promoter region using mouse liver genomic DNA, the methylation-specific restriction enzyme (HpaII), and disulfide conversion. Our results showed that two possible CpG methylation sites were methylated and demethylated by Wy-14,643 treatment. This study indicates that epigenetic change at the Gadd45b promoter is critical for Gadd45b induction.
authors.affiliation: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea. Electronic address: junghwan.kim@gnu.ac.kr.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea.
authors.forename: Lilik Duwi
authors.initials: LD
authors.lastname: Wahyudi
authors.affiliation: Department of Biochemistry, Chungnam National University, Daejeon 34134, Republic of Korea.
authors.forename: Kee K
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics*; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D047493:PPAR alpha; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins
keywords: CpG methylation; Gadd45b; PPARα