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Final Copy 2020 01 23 Kenn This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Kennedy, Clare L Title: An investigation into the genomic actions of glucocorticoid binding receptors in the rat brain following acute stress and circadian influences General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. An investigation into the genomic actions of glucocorticoid binding receptors in the rat brain following acute stress and circadian influences Clare Linda Kennedy A thesis submitted to the University of Bristol in accordance with the requirements of the degree of Doctor of Philosophy in the Faculty of Health Sciences, Bristol Medical School September 2019 Word Count: 63, 581 Abstract Glucocorticoid (GC) hormones secreted upon activation of the HPA axis following stress or circadian input are vital regulators of many important physiological processes. In the brain, genomically acting mineralocorticoid receptors (MRs) and glucocorticoid receptor (GRs), orchestrate the cellular and molecular effects of GCs. Upon receptor occupancy, MRs and GRs translocate to the nucleus where they bind the DNA to transactivate or transrepress GC-target gene expression. Here, we conducted hippocampal ChIP- and RNA-seq to investigate the genome-wide binding of MRs and GRs and the transcriptomic response following elevations in corticosterone, the primary GC in the rat, in response to an acute stressor (Forced swimming – FS) or the circadian rise of GC secretion. ChIP-seq revealed a strikingly distinct profile of MR- and/or GR-binding to over 1,000 loci, while RNA-seq identified transcriptional responses in over 1,000 genes. Cross-correlation of both datasets was carried out for the first time, while extensive pathway analysis highlighted many promising novel targets for further exploration. Of these targets, we further investigated the Krüppel-like factors (KLFs) in a separate cohort of rats while validating findings of ChIP- and RNA-seq. We extended our examination to other brain regions such as the amygdala, PFC and neocortex which showed substantial MR DNA-binding in these regions despite previous reports describing a localised expression of this receptor primarily in the hippocampus. Subsequently, we investigated whether the increases in binding were in fact the underlying events responsible for the observed transcriptional responses by blocking the actions of genomically acting MRs and GRs, using receptor antagonists, inhibitors of corticosterone synthesis and surgical adrenalectomy. This thesis has provided novel insights into the genomic actions of MRs and GRs under physiological conditions of relevance for GC secretion, while providing the groundwork for future experiments aiming to elucidate further the genomic mechanisms underlying GC hormone action in the brain. i Acknowledgements First and foremost, I would like to thank my supervisor, Professor Hans Reul, for the opportunity to carry out my PhD in his research group, and for his guidance, support and input throughout these 4 years. I am incredibly grateful to the Wellcome Trust and BBSRC; who have provided the funding to support my work. I would like to thank our collaborators at the Wellcome Centre for Human Genetics, Oxford; especially Silvia. I would like to thank all past and present members of the Reul group. Karen; I could never thank you enough for being my unofficial second supervisor, counsellor and general life saver. Thank you for offering me so much support and guidance and being a fantastic colleague and friend. Emily; these past few years would not have been half as enjoyable without you there to make me laugh. Thank you for always listening to me vent and for proofreading my thesis with your eagle eye. I am going to miss dancing around the lab to Radio1 together and being the victim of your sarcasm! I would also like to thank my lovely colleagues at the Dorothy Hodgkin Building. Dagmara and Paul; without you both, we would all be lost! Astrid, thank you for your kindness and encouragement. Ben, Matt and George, our Friday pub trips, and general excursions have kept me sane; we make a truly fantastic clique. Mom and Dad, thank supporting me throughout this PhD and in my next academic adventure (Bioemphemetics is a far better spelling). Fred, my winning ticket, thank you for everything. ii Author’s Declaration I declare that the work in this thesis was carried out in accordance with the requirements of the University’s Regulations and Code of Practice for Research Degree Programmes and that it has not been submitted for any other academic award. Except where indicated by specific reference in the text, the work is the candidate’s own work. Work done in collaboration with, or with the assistance of, others, is indicated as such. Any views expressed in the dissertation are those of the author. SIGNED:……………………………………………………………..DATE:…………………………. iii Abbreviations 3C Chromatin conformation capture 6-FAM 6-Carboxyfluorescein A Adenine Aβ Amyloid-beta ACTH Adrenocorticotropic hormone ACTHR ACTH receptor ADX Adrenalectomy AEBSF 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride AF-1 Activation function-1 AF-2 Activation function-2 AmPFC Anterior mPFC AP1 Activation protein 1 ASM Airway smooth muscle ATOH1 Atonal BHLH Transcription Factor AVP Arginine vasopressin Bace1 Beta-Secretase 1 BAFs BRM/BRG1 associated factors BBB Blood-brain barrier Bdnf Brain-derived neurotrophic factor BLA Basolateral nucleus of the amygdala BLAM Baseline a.m. BLPM Baseline p.m. Bmal1 Brain and Muscle ARNT-Like 1 BOLD Blood oxygenation level dependent Bps Base pairs BRM Brahma BRG1 Brahma-related gene 1 iv BTEB Basic transcription element-binding protein C Cytosine CA Cornu ammonis cAMP Cyclic adenosine mono phosphate CBG Corticosteroid-binding globulin CBP CREB binding protein CCK Cholecystokinin CE Circadian exclusive CeA Central nucleus of the amygdala CFL1 Cofilin 1 ChIP Chromatin immunoprecipitation ChIP-seq ChIP-sequencing CLOCK Clock circadian regulator CNS Central nervous system CON Constitutive CORT Corticosterone CREB cAMP response element binding protein CRH Corticotropin-releasing hormone CRX Con-Rod Homeobox CRY Cryptochrome circadian regulator CRY2 Cryptochrome circadian regulator 2 CSF Cerebrospinal fluid CYP Cytochrome P450 family CyPA Cyclophilin A DAVID Database for Annotation, Visualization and Integrated Discovery DBD DNA-binding domain DEX Dexamethasone DG Dentate gyrus v Disc1 Disrupted-in-schizophrenia 1 DHEA Dehydroepiandrosterone DHEAS Dehydroepiandrosterone sulphate ester DOC 11-deoxycorticosterone Dlx2 Distal-Less Homeobox 2 DNA Deoxyribonucleic acid dNTP deoxyribonucleotide triphosphate DST Dexamethasone suppression test EC Endothelial cell EDTA Ethylenediaminetetraacetic acid EGR Early growth response EMAS Electrophoretic mobility shift assay Erbb4 Erb-B2 Receptor Tyrosine Kinase 4 ERK Extracellular regulated kinase ERK1/2 Extracellular regulated kinase ½ ESR Estrogen Receptor EWSR1-FLI1 EWS RNA Binding Protein 1-Fli-1 Proto-Oncogene, ETS transcription factor exRNA exonic RNA FAIRE Formaldehyde assisted isolation of regulatory elements FDR False discovery rate Fkbp4 FK506 binding protein 52 Fkbp5 FK506 binding protein 51 fMRI Functional magnetic resonance imaging Fos Fos Proto-Oncogene AP-1 Transcription Factor Subunit FOX Forkhead box FOXO3A Forkhead box O3A FS Forced swimming G Guanine vi GC Glucocorticoid GABA Gamma aminobutyric acid GABAA Gamma aminobutyric acid subunit A GAD Glutamic acid decarboxylase GAD65 Glutamic acid decarboxylase 65 GAD67 Glutamic acid decarboxylase 67 Gapdh Glyceraldehyde 3-phosphate dehydrogenase GFAP Glial fibrillary acidic protein GO Gene Ontology GR Glucocorticoid receptor GRox Glucocorticoid receptor over-expressing GRE Glucocorticoid response element GRIA2 Glutamate ionotropic receptor AMPA type subunit 2 GRIN1 Glutamate ionotropic receptor NMDA type subunit 1 GRIN2B Glutamate ionotropic receptor NMDA type subunit 2B H Histone HAT Histone acetyltransferase HBMEC Human brain microvascular endothelial cells HDAC Histone deacetylase hGR human GR hnRNA Heteronuclear RNA Homer3 Homer Scaffold Protein 3 HR Hinge region HSD3B Hydroxy-delta-5-steroid-dehydrogenase, 3-beta Hsp Heat shock protein HPA Hypothalamic-pituitary-adrenal Hprt1 Hypoxanthine phosphoribosyltransferase 1 inRNA intronic RNA vii i.p. Intraperitoneal IPA Ingenuity pathway analysis K Lysine Kbs
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