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Open Access Highly Accessed Research article

A genome-wide signature of glucocorticoid receptor binding in neuronal PC12 cells

J Annelies E Polman1, Jennifer E Welten1, Danny S Bosch1, Robert T de Jonge1, Judit Balog2, Silvère M van der Maarel2, E Ronald de Kloet1 and Nicole A Datson12*

Author Affiliations

1 Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, 2333 CC, the Netherlands

2 Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZC, the Netherlands

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BMC Neuroscience 2012, 13:118  doi:10.1186/1471-2202-13-118

Published: 3 October 2012

Abstract

Background

Glucocorticoids, secreted by the adrenals in response to stress, profoundly affect structure and plasticity of neurons. Glucocorticoid action in neurons is mediated by glucocorticoid receptors (GR) that operate as transcription factors in the regulation of gene expression and either bind directly to genomic glucocorticoid response elements (GREs) or indirectly to the genome via interactions with bound transcription factors. These two modes of action, respectively called transactivation and transrepression, result in the regulation of a wide variety of genes important for neuronal function. The objective of the present study was to identify genome-wide glucocorticoid receptor binding sites in neuronal PC12 cells using Chromatin ImmunoPrecipitation combined with next generation sequencing (ChIP-Seq).

Results

In total we identified 1183 genomic binding sites of GR, the majority of which were novel and not identified in other ChIP-Seq studies on GR binding. More than half (58%) of the binding sites contained a GRE. The remaining 42% of the GBS did not harbour a GRE and therefore likely bind GR via an intermediate transcription factor tethering GR to the DNA. While the GRE-containing binding sites were more often located nearby genes involved in general cell functions and processes such as apoptosis, cell motion, protein dimerization activity and vasculature development, the binding sites without a GRE were located nearby genes with a clear role in neuronal processes such as neuron projection morphogenesis, neuron projection regeneration, synaptic transmission and catecholamine biosynthetic process. A closer look at the sequence of the GR binding sites revealed the presence of several motifs for transcription factors that are highly divergent from those previously linked to GR-signaling, including Gabpa, Prrx2, Zfp281, Gata1 and Zbtb3. These transcription factors may represent novel crosstalk partners of GR in a neuronal context.

Conclusions

Here we present the first genome-wide inventory of GR-binding sites in a neuronal context. These results provide an exciting first global view into neuronal GR targets and the neuron-specific modes of GR action and potentially contributes to our understanding of glucocorticoid action in the brain.

Keywords:
Glucocorticoid receptor; Neuronal context; Glucocorticoid response element; PC12 cells; ChIP-Seq