Genomic regulation of Krüppel-like-factor family members by corticosteroid receptors in the rat brain

Clare L M Kennedy; Emily M Price; Karen R Mifsud; Silvia Salatino; Eshita Sharma; Simon Engledow; John Broxholme; Hannah M Goss; Johannes M H M Reul

doi:10.1016/j.ynstr.2023.100532

Genomic regulation of Krüppel-like-factor family members by corticosteroid receptors in the rat brain

Neurobiol Stress. 2023 Mar 7:23:100532. doi: 10.1016/j.ynstr.2023.100532. eCollection 2023 Mar.

Authors

Clare L M Kennedy¹, Emily M Price¹, Karen R Mifsud¹, Silvia Salatino², Eshita Sharma², Simon Engledow², John Broxholme², Hannah M Goss¹, Johannes M H M Reul¹

Affiliations

¹ Neuro-Epigenetics Research Group, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, United Kingdom.
² Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.

Abstract

Hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) mediate glucocorticoid hormone (GC) action in the hippocampus. These receptors bind to glucocorticoid responsive elements (GREs) within target genes, eliciting transcriptional effects in response to stress and circadian variation. Until recently, little was known about the genome-wide targets of hippocampal MRs and GRs under physiological conditions. Following on from our genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus, we investigated the Krüppel-like factors (KLFs) as targets of MRs and GRs throughout the brain under circadian variation and after acute stress. In particular, Klf2, Klf9 and Klf15 are known to be stress and/or GC responsive and play a role in neurobiological processes including synaptic plasticity and neuronal differentiation. We found increased binding of MR and GR to GREs within Klf2, Klf9 and Klf15 in the hippocampus, amygdala, prefrontal cortex, and neocortex after acute stress and resulting from circadian variation, which was accompanied by upregulation of corresponding hnRNA and mRNA levels. Adrenalectomy abolished transcriptional upregulation of specific Klf genes. These results show that MRs and GRs regulate Klf gene expression throughout the brain following exposure to acute stress or in response to circadian variation, likely alongside other transcription factors.