Abstract
Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding.
Highlights
The mineralocorticoid receptor (MR) regulates stress coping and has gained significant attention in the field of psychopathology
We found that binding sites for NeuroD factors were present selectively near MR-bound loci, and confirmed Neurod2 binding near MR-bound but not glucocorticoid receptor (GR)-bound glucocorticoid response element (GRE) [9]
In order to define the mechanism behind the NeuroD potentiation of glucocorticoid signaling in more detail, we first tested whether MR binding to its hippocampal DNA targets affects local GR and Neurod2 binding
Summary
The mineralocorticoid receptor (MR) regulates stress coping and has gained significant attention in the field of psychopathology. Being part of the nuclear receptor family, MR and GR function as ligand-activated transcription factors, binding the glucocorticoid response element (GRE) at the DNA to mediate transcriptional changes. Even though the two receptors share their ligand cortisol/corticosterone (albeit with a different affinity) and recognize the same motif, receptor-specific binding loci exist as demonstrated in the rat hippocampus [9]. This suggests that other factors might be necessary to guide MR/GR-specific binding and subsequent transcriptional effects. As the MyoD proteins are better understood in terms of functional domains [12], we examined transcriptional modulation by bHLH factors at the MyoD/NeuroD shared motif to unravel the interaction between NeuroD and MR here. Our data show that at MR target loci both GR and Neurod binding seem independent of MR binding, and it is likely the chromatin remodeling effect of NeuroD is responsible for the transcriptional potentiation
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