Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Abstract: Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone receptor (Pgr)] with sets of steroid target genes that were identified in single brain regions. These coexpression relationships were also present in distinct other brain regions, suggestive of as yet unidentified coordinate regulation of brain regions by, for example, glucocorticoids and estrogens. Second, coexpression of a set of 62 known NR coregulators and the six steroid receptors in 12 nonoverlapping mouse brain regions revealed selective downstream pathways, such as Pak6 as a mediator for the effects of *Ar* and *Gr* on dopaminergic transmission. Third, Magel2 and Irs4 were identified and validated as strongly responsive targets to the estrogen diethylstilbestrol in the mouse hypothalamus. The brain- and genome-wide correlations of mRNA expression levels of six steroid receptors that we provide constitute a rich resource for further predictions and understanding of brain modulation by steroid hormones.

 Cover mention and Commentary
Ahmed Mahfouz, Boudewijn Lelieveldt, Aldo Grefhorst, Lisa TCM van Weert, Isabel M Mol, et al. Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions. PNAS, 113(10): pp. 2738–2743, 2016.
@article { bib:2016_pnas_steroids,
author = { Ahmed Mahfouz and Boudewijn Lelieveldt and Aldo Grefhorst and Lisa TCM van Weert and Isabel M Mol and Hetty CM Sips and Jos{\ K van den Heuvel and Nicole A Datson and Jenny A Visser and Marcel Reinders and Onno Meijer },
title = { Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions },
journal = { PNAS },
volume = { 113 },
number = { 10 },
pages = { 2738 -- 2743 },
year = { 2016 },
doi = { 10.1073/pnas.1520376113 },
}
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