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IUGR increases chromatin-remodeling factor Brg1 expression and binding to GR exon 1.7 promoter in newborn male rat hippocampus. Am J Physiol Regul Integr Comp Physiol 2015 Jul 15;309(2):R119-27

Date

05/15/2015

Pubmed ID

25972460

DOI

10.1152/ajpregu.00495.2014

Scopus ID

2-s2.0-84937440345   4 Citations

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.

Author List

Ke X, McKnight RA, Gracey Maniar LE, Sun Y, Callaway CW, Majnik A, Lane RH, Cohen SS

Author

Susan Cohen MD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Binding Sites
Chromatin Assembly and Disassembly
DNA Helicases
Disease Models, Animal
Exons
Fetal Growth Retardation
Gene Expression Regulation, Developmental
Hippocampus
Male
Nuclear Proteins
Nucleosomes
Promoter Regions, Genetic
RNA Polymerase II
Rats
Receptors, Glucocorticoid
Sp1 Transcription Factor
Transcription Factors
Transcription Initiation Site
Transcription, Genetic
Up-Regulation