Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors

Karen R Mifsud, Clare L M Kennedy, Silvia Salatino, Eshita Sharma, Emily M Price, Samantha N Haque, Andriana Gialeli, Hannah M Goss, Polina E Panchenko, John Broxholme, Simon Engledow, Helen Lockstone, Oscar Cordero Llana, Johannes M H M Reul

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Abstract

Glucocorticoid hormones (GCs) - acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) - are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments.

Original languageEnglish
Article number4737
JournalNature Communications
Volume12
Issue number1
Early online date6 Aug 2021
DOIs
Publication statusE-pub ahead of print - 6 Aug 2021

Bibliographical note

Funding Information:
This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC; Grant Numbers BB/K007408/1 and BB/N015045/1), a Wellcome Trust Neural Dynamics PhD studentship (to C.L.M.K.), and BBSRC SWBio DTP PhD studentships (to E.M.P. and S.N.H). We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (supported by the Wellcome Trust Core Award Grant Number 203141/ Z/16/Z) for the generation and initial processing of the sequencing data. We would like to thank Dr C Kelly, Dr S Rowlands and Ms R Hills at the Cardiff SWIFT human fetal tissue bank (University of Cardiff, Cardiff, UK) for their help with procurement and collection of fetal tissue samples.

Publisher Copyright:
© 2021, The Author(s).

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