SFEBES2015 Poster Presentations Steroids (49 abstracts)
Genome-wide binding analysis of glucocorticoid receptors in the rat hippocampus in response to corticosterone and stress
Benjamin P Flynn 1 , John R Pooley 1, , Yvonne M Kershaw 1 , Songjoon Baek 2 , Lars Grontved 2 , Michael J Guertin 2 , Gordon L Hager 2 , Stafford L Lightman 1 & Becky L Conway-Campbell 1
1University of Bristol, Bristol, UK; 2National Institute of Health, Maryland, USA.
Glucocorticoids act via the glucocorticoid receptor (GR). Upon ligand binding, GR translocates to the nucleus and binds directly to glucocorticoid responsive elements (GREs) to regulate transcriptional output. Glucocorticoid secretion increases in response to stress to affect transcriptional output within specific areas of the brain including the hippocampus (HC). Therefore, here we assess changes in genome-wide GR chromatin binding profiles in the rat HC in response to a glucocorticoid rise, with or without an acute stress in order to identify significant motifs at the sites of GR binding. Male ADX Sprague Dawley rats were sacrificed after a 30 min glucocorticoid infusion with/without a 30 min restraint stress and HC dissected for chromatin immunoprecipitation assays (ChIP) using a GR antibody cocktail. GR binding sites and DNA motifs were identified, including the previously characterised Per1 regulatory sites. Novel sites were identified proximal to Bdnf, SGK1 and Camk2a. Interestingly, there was no significant difference in peak tag density between basal and stress groups. HOMER analysis identified motifs for GRE, NF1 and NeuroD1 as top recurring motifs at 53, 62 and 18% respectively. The motifs identified in this study represent targets for further study. NeuroD1 in particular is thought to be involved in learning and memory. Therefore NeuroD1 is an interesting target for future analysis of GC-regulated HC function. BDNF and Camk2a mRNA levels have previously been described as regulated in response to stress. Interestingly our findings have shown no change at the point of GR binding to these GREs and little change to the genome-wide chromatin binding profile in response to acute stress compared to increased glucocorticoids in the absence of a concomitant stressor. These findings suggests that glucocorticoid dependent stress regulation in the HC is primarily regulated by the glucocorticoid rise, and not further modulated other stress associated factors in our ADX rat model.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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