Genome-wide coexpression of steroid receptors in the mouse brain

Identifying signaling pathways and functionally coordinated regions

Journal article (2016)

Authors

A.M.E.T.A. Mahfouz Pattern Recognition and Bioinformatics - EEMCS , Leiden University Medical Center
B.P.F. Lelieveldt Pattern Recognition and Bioinformatics - EEMCS , Leiden University Medical Center
Onno C. Meijer Leiden University Medical Center
Aldo Grefhorst Erasmus MC
A.A.M. Van Weert Leiden University Medical Center
Isabel M. Mol Leiden University Medical Center
Hetty C.M. Sips Leiden University Medical Center
José K. van den Heuvel Leiden University Medical Center
Nicole A. Datson Leiden University Medical Center
Jenny A. Visser Erasmus MC
M.J.T. Reinders Pattern Recognition and Bioinformatics - EEMCS
Research Group
Pattern Recognition and Bioinformatics (EEMCS) (TU Delft)
Transcription regulation Estrogens Neuroendocrinology Nuclear receptors Glucocorticoids
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Published Date

2016

Language

English

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Faculty

Electrical Engineering, Mathematics and Computer Science

Department

Intelligent Systems

Research Group

Pattern Recognition and Bioinformatics

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.