Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Mar 8;113(10):2738-43.
doi: 10.1073/pnas.1520376113. Epub 2016 Jan 25.

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

Ahmed Mahfouz  1 , Boudewijn P F Lelieveldt  2 , Aldo Grefhorst  3 , Lisa T C M van Weert  4 , Isabel M Mol  4 , Hetty C M Sips  4 , José K van den Heuvel  4 , Nicole A Datson  5 , Jenny A Visser  3 , Marcel J T Reinders  6 , Onno C Meijer  4
Affiliations

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

Ahmed Mahfouz et al. Proc Natl Acad Sci U S A. .

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.

Keywords: estrogens; glucocorticoids; neuroendocrinology; nuclear receptors; transcription regulation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Expression of steroid receptors in the mouse brain. (A) Expression of six steroid receptors across the 12 brain regions. Reported values are the average expression energy per region normalized to the average expression across the whole brain and then log2-transformed. (B) Example sagittal sections from the Allen Brain Atlas (4) showing the ISH (Left), expression mask (Middle), and corresponding atlas section (Right) of Esr1 in the HY (Top) and Gr in the hippocampus (Bottom). Red arrows indicate the MPO, ARH, CA1, and DG.
Fig. 2.
Fig. 2.
Coexpression of GC-responsive genes and Gr in the hippocampus. (A) Coexpression of four GC-responsive gene sets with Gr in the whole brain, hippocampus, DG, CA1, CA2, and CA3. (B) Coexpression of four GC-responsive gene sets with Gr across the whole brain, as well as the 12 major brain structures. All bars indicate the −log10 of the Wilcoxon rank sum test, and the dashed line indicates the significance level at P = 0.05.
Fig. 3.
Fig. 3.
Coexpression of sexually dimorphic genes and Esr1 in the HY. (A) Coexpression of 15 sexually dimorphic genes with Esr1 across the mouse brain. (B) Coexpression of the 15 sexually dimorphic genes with the six steroid receptors across the whole brain, as well as the HY. All bars indicate the −log10 of the Wilcoxon rank sum test, and the dashed line indicates the significance level at P = 0.05.
Fig. 4.
Fig. 4.
Coexpression of coregulators and steroid receptors. (A) Expression of 62 coregulators in 12 brain regions. Reported values are the average expression energy per region normalized to the average expression across the whole brain and then log2-transformed. Coexpression ranks of the 62 coregulators with Ar (B), Gr (C), and Mr (D). Dark red corresponds to high rank (i.e., strong coexpression). (E) Rank sum of the coexpression rank of each coregulator with Ar in the dopaminergic regions (VTA and SN).
Fig. S1.
Fig. S1.
Dopaminergic system in the mouse brain. A coronal section from the Allen Brain Atlas (4) shows the VTA and SN (thick black contour) that composes the dopaminergic system, indicated.
Fig. S2.
Fig. S2.
Expression of steroid receptors and coregulators in the dopaminergic system. The expression of six steroid receptors (A) and 62 coregulators (B) in the VTA, SN reticular part (SNr), and SN compact part (SNc). Reported values are the average expression energy per region normalized to the average expression across the whole brain and then log2-transformed.
Fig. 5.
Fig. 5.
Highly coexpressed genes are potential steroid targets. (A) Coronal ISH sections showing the expression of Esr1, Irs4, and Magel2. (Scale bars, 600 μm.) Data taken from the Allen Brain Atlas (4). Response of Irs4 (B) and Magel2 (C) to DES treatment in castrated mice in the MPO and ARH using dISH. (D) dISH of Esr1 (red) and Irs4 (green) in the anterior HY. (Scale bars, 10 μm. Magnification, 100×.) (E) dISH of Esr1 (red) and Magel2 (green) in the anterior HY. (Scale bars, 10 μm. Magnification, 100×.) mRNA expression in ISH was quantified as the percentage of the image surface with positive signal. Reported P values are calculated with a one-sided, two-sample t test with a significant level at P < 0.05.
Fig. S3.
Fig. S3.
Down-regulation of mRNA levels of Esr1 in response to DES treatment. The mRNA levels of Esr1, measured using dISH, were significantly down-regulated (P < 0.05) in the anterior (MPO) and posterior (ARH) HY of the control and DES-treated mice.
Fig. S4.
Fig. S4.
Response of Esr1-coexpressed genes to DES treatment. The mRNA levels of Adck4, Unc5, Ngb, and Gdpd2 were measured using dISH in the anterior (MPO) and posterior (ARH) HY of the control and DES-treated mice.
Fig. S5.
Fig. S5.
Validating GR targets in hippocampus using ChIP-Seq. Examples of GR binding sites to genes strongly coexpressed with Gr in the hippocampus: Itpr1 (A), Ttyh1 (B), Ptn (C), and Hecw2 (D). For each gene, a genomic region of 32 kb centered around the identified peak is shown using the Integrative Genomics Viewer (46). Black arrows indicate the intergenic peaks identified within the gene.
See this image and copyright information in PMC

Comment in

  • Coexpression profiles reveal hidden gene networks.
    Chachlaki K, Prévot V. Chachlaki K, et al. Proc Natl Acad Sci U S A. 2016 Mar 8;113(10):2563-5. doi: 10.1073/pnas.1600717113. Epub 2016 Feb 23. Proc Natl Acad Sci U S A. 2016. PMID: 26908874 Free PMC article. No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Stanisić V, Lonard DM, O’Malley BW. Modulation of steroid hormone receptor activity. Prog Brain Res. 2010;181:153–176. - PubMed
    1. de Kloet ER, Joëls M, Holsboer F. Stress and the brain: From adaptation to disease. Nat Rev Neurosci. 2005;6(6):463–475. - PubMed
    1. Toffoletto S, Lanzenberger R, Gingnell M, Sundström-Poromaa I, Comasco E. Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: A systematic review. Psychoneuroendocrinology. 2014;50:28–52. - PubMed
    1. Lein ES, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445(7124):168–176. - PubMed
    1. John S, et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet. 2011;43(3):264–268. - PMC - PubMed

Publication types

LinkOut - more resources