title: IUGR increases chromatin-remodeling factor Brg1 expression and binding to GR exon 1.7 promoter in newborn male rat hippocampus.
abstract: Intrauterine growth restriction (IUGR) increases the risk for neurodevelopment delay and neuroendocrine reprogramming in both humans and rats. Neuroendocrine reprogramming involves the glucocorticoid receptor (GR) gene that is epigenetically regulated in the hippocampus. Using a well-characterized rodent model, we have previously shown that IUGR increases GR exon 1.7 mRNA variant and total GR expressions in male rat pup hippocampus. Epigenetic regulation of GR transcription may involve chromatin remodeling of the GR gene. A key chromatin remodeler is Brahma-related gene-1(Brg1), a member of the ATP-dependent SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. Brg1 regulates gene expression by affecting nucleosome repositioning and recruiting transcriptional components to target promoters. We hypothesized that IUGR would increase hippocampal Brg1 expression and binding to GR exon 1.7 promoter, as well as alter nucleosome positioning over GR promoters in newborn male pups. Further, we hypothesized that IUGR would lead to accumulation of specificity protein 1 (Sp1) and RNA pol II at GR exon 1.7 promoter. Indeed, we found that IUGR increased Brg1 expression and binding to GR exon 1.7 promoter. We also found that increased Brg1 binding to GR exon 1.7 promoter was associated with accumulation of Sp1 and RNA pol II carboxy terminal domain pSer-5 (a marker of active transcription). Furthermore, the transcription start site of GR exon 1.7 was located within a nucleosome-depleted region. We speculate that changes in hippocampal Brg1 expression mediate GR expression and subsequently trigger neuroendocrine reprogramming in male IUGR rats.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah;
authors.forename: Xingrao
authors.initials: X
authors.lastname: Ke
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah;
authors.forename: Robert A
authors.initials: RA
authors.lastname: McKnight
authors.affiliation: Genetics, Stanford University School of Medicine, Stanford, California; and.
authors.forename: Lia E
authors.initials: LE
authors.lastname: Gracey Maniar
authors.affiliation: Bioinformatics-Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah;
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Callaway
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Amber
authors.initials: A
authors.lastname: Majnik
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lane
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin; scohen@mcw.edu.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Cohen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005091:Exons; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C542344:NR3C1 protein, rat; D009687:Nuclear Proteins; D009707:Nucleosomes; D011965:Receptors, Glucocorticoid; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D012319:RNA Polymerase II; C578929:Smarca4 protein, rat; D004265:DNA Helicases
keywords: Brahma-related gene 1; glucocorticoid receptor; hippocampus; intrauterine growth restriction