title: 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.
authors.affiliation: Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Delft Bioinformatics Laboratory, Delft University of Technology, 2628 CD Delft, The Netherlands; a.mahfouz@lumc.nl.
authors.forename: Ahmed
authors.identifier: http://orcid.org/0000-0001-8601-2149
authors.initials: A
authors.lastname: Mahfouz
authors.affiliation: Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Delft Bioinformatics Laboratory, Delft University of Technology, 2628 CD Delft, The Netherlands;
authors.forename: Boudewijn P F
authors.initials: BP
authors.lastname: Lelieveldt
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands;
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
authors.forename: Lisa T C M
authors.initials: LT
authors.lastname: van Weert
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Mol
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
authors.forename: Hetty C M
authors.initials: HC
authors.lastname: Sips
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
authors.forename: José K
authors.initials: JK
authors.lastname: van den Heuvel
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Centre for Drug Research/Leiden University Medical Center, Leiden 2333 CC, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Datson
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands;
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Visser
authors.affiliation: Delft Bioinformatics Laboratory, Delft University of Technology, 2628 CD Delft, The Netherlands;
authors.forename: Marcel J T
authors.identifier: http://orcid.org/0000-0002-1148-1562
authors.initials: MJ
authors.lastname: Reinders
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
authors.forename: Onno C
authors.initials: OC
authors.lastname: Meijer
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D016678:Genome / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008810:Mice, Inbred C57BL; D011980:Receptors, Progesterone / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D011987:Receptors, Steroid
keywords: estrogens; glucocorticoids; neuroendocrinology; nuclear receptors; transcription regulation
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