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Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes

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Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular Dopamine triggers CTCF-dependent morphological and genomic remodeling of astrocytes Ashley Galloway1,2, Adewale Adeluyi3, Bernadette O'Donovan1, Miranda L Fisher3, Chintada Nageswara Rao3, Peyton Critchfield1, Mathew Sajish3, Jill R Turner3 and Pavel I. Ortinski1 1Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA. 2Integrated Program in Biomedical Sciences, University of South Carolina, Columbia, South Carolina, USA. 3Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA. DOI: 10.1523/JNEUROSCI.3349-17.2018 Received: 27 November 2017 Revised: 29 March 2018 Accepted: 19 April 2018 Published: 30 April 2018 Author contributions: A.G. and P.I.O. designed research; A.G., A.A., B.O., M.F., C.N.R., and P.C. performed research; A.G., A.A., B.O., M.F., P.C., M.S., and J.R.T. analyzed data; A.G., B.O., M.S., J.R.T., and P.I.O. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. We would like to recognize Dr. Rosemarie Booze and Dr. Marina Aksenova (University of South Carolina) for help with generation of hippocampal astrocyte cultures. This work was supported by the National Institutes of Health grants DA031747, DA041513 (P.I.O.), DA032681 (J.R.T.) Corresponding Author: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.3349-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors 1 Title: 2 Dopamine triggers CTCF-dependent morphological and genomic remodeling of astrocytes 3 Authors: 4 Ashley Galloway1,2,*, Adewale Adeluyi3,*, Bernadette O’Donovan1, Miranda L Fisher3, Chintada 5 Nageswara Rao3, Peyton Critchfield1, Mathew Sajish3, Jill R Turner3,* , Pavel I. Ortinski1,*,# 6 Affiliations: 7 1 Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of 8 Medicine, Columbia, South Carolina, USA. 9 2 Integrated Program in Biomedical Sciences, University of South Carolina, Columbia, South Carolina, 10 USA. 11 3Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, 12 University of South Carolina, Columbia, South Carolina, USA. 13 * Authors contributed equally. 14 # Corresponding Author: [email protected] 15 Funding: This work was supported by the National Institutes of Health grants DA031747, DA041513 16 (P.I.O.), DA032681 (J.R.T.) 17 Competing Interests Statement: The authors declare no competing financial interests. 18 Acknowledgements: We would like to recognize Dr. Rosemarie Booze and Dr. Marina Aksenova 19 (University of South Carolina) for help with generation of hippocampal astrocyte cultures. 20 Word Count: 21 Total: 6033 22 Abstract: 192 23 Introduction: 589 24 Materials and Methods: 1699 25 Results: 2073 26 Discussion: 1479 27 28 1 29 ABSTRACT 30 31 Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the 32 brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are 33 not well-established. We found that extracellular dopamine triggered rapid concentration-dependent 34 stellation of astrocytic processes that was not a result of dopamine oxidation, but instead, relied on 35 both cAMP-dependent and cAMP-independent dopamine receptor signaling. This was accompanied 36 by reduced duration and increased frequency of astrocytic Ca2+ transients, but little effect on 37 astrocytic voltage-gated potassium channel currents. To isolate possible mechanisms underlying 38 these structural and functional changes, we used whole-genome RNA sequencing and found 39 prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) 40 motif, suggesting involvement of chromatin restructuring in the nucleus. CTCF binding to promoter 41 sites bi-directionally regulates gene transcription and depends on activation of poly-ADP-ribose 42 polymerase 1 (PARP1). Accordingly, antagonism of PARP1 occluded dopamine-induced changes, 43 whereas a PARP1 agonist facilitated dopamine-induced changes on its own. These results indicate 44 that astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring 45 and concerted expression of gene networks. Our findings propose epigenetic regulation of chromatin 46 landscape as a critical factor in the rapid astrocyte response to dopamine. 47 48 Significance Statement: Although dopamine is widely recognized for its role in modulating neuronal 49 responses both in healthy and disease states, little is known about dopamine effects at non-neuronal 50 cells in the brain. To address this gap, we performed whole-genome sequencing of astrocytes 51 exposed to elevated extracellular dopamine and combined it with evaluation of effects on astrocyte 52 morphology and function. We demonstrate a temporally dynamic pattern of genomic plasticity that 53 triggers pronounced changes in astrocyte morphology and function. We further show that this 54 plasticity depends on activation of genes sensitive to DNA-binding protein CTCF. Our results propose 55 that a broad pattern of astrocyte responses to dopamine specifically relies on CTCF-dependent gene 56 networks. 57 58 59 60 2 61 INTRODUCTION 62 Astrocytes are a major subpopulation of the brain glial cells that mediate multiple functions, including 63 metabolic, ionic and pH homeostasis, trophic support of neurons, antioxidant defense, the 64 establishment and maintenance of the blood brain barrier, and regulation of neuronal activity (Kandel 65 et al., 2012; Oberheim et al., 2012; Clarke and Barres, 2013; Fattore et al., 2002; Clark et al., 2013; 66 Zamanian et al., 2012; Freeman 2010; Bushong et al. 2002; Perea et al., 2009). Such functional 67 diversity is accompanied by morphological heterogeneity that varies with development and across 68 brain regions (Raff et al., 1983; Miller and Raff, 1984; Khakh and Sofroniew, 2015; Chai et al., 2017). 69 For example, astrocytic domain boundaries are observed later, but not early in development 70 (Bushong et al., 2004) and astrocytes in the striatum have significantly more processes than 71 hippocampal astrocytes (Chai et al., 2017; Khakh and Sofroniew, 2015) 72 In cultured conditions, two astrocytic phenotypes have been distinguished based on 73 morphological characteristics: type I cells have a flat polygonal appearance with a “mesh” of 74 intertwined fine processes and resemble astrocytes populating grey matter; type II cells have clearly 75 defined thicker “stellated” processes and resemble the astrocytes arranged along white matter tracts 76 (Raff et al., 1983; Oberheim et al., 2012). Standard protocols that use serum-supplemented culture 77 media result in predominantly polygonal, type 1 astrocytes. However, these astrocytes can be 78 transformed into a stellated morphology by exposure to cAMP analogs (Won and Oh, 2000; Moonen 79 et al., 1975; Paco et al., 2016). The cAMP-induced morphological transformation occurs within 2 80 hours and is associated with decreased cell body area and extension of distinct thick processes. 81 Dopamine may trigger cAMP production via activation of D1-like dopamine receptors, 82 expressed by astrocytes along with other dopamine receptor subtypes (Miyazaki et al., 2004; Shao et 83 al., 2013; Mladinov et al., 2010; Khan et al., 2001; Nagatomo et al. 2017). D1-induced production of 84 cAMP has been linked to release of astrocytic Ca2+ from internal stores, an important hallmark of 85 astrocyte-to-astrocyte, astrocyte-to-neuron, and astrocyte-to-vasculature signaling (Jennings et al., 86 2017; Chai et al., 2017). Indeed, both structural and functional astrocyte adaptations have been 87 reported in models of neurologic disease linked to dysregulated dopamine signaling. For example, 88 Parkinson’s disease is associated with hypertrophy of astrocytic processes, a feature of reactive 89 astrocytosis (Booth et al., 2017), while cocaine use has been linked to a reduction of astrocyte 90 surface area and reduced interaction with synapses (Scofield et al., 2016). Furthermore, a number of 91 studies have demonstrated that dopamine-induced increase in astrocytic Ca2+ impacts cellular 92 respiration mechanisms coupled to PARP1 and sirtuin activation (Requardt et al., 2010; Requardt et 93 al., 2012; Gupte et al., 2017; Verdin 2015). PARP1 is a critical co-factor for NAD+-dependent poly- 3 94 ADP-ribosylation of CCCTC binding factor (CTCF) which promotes CTCF binding to target genes (Yu 95 et al., 2004; Ong et al., 2013; Han et al., 2017). Recent studies have shown that CTCF regulates both 96 chromatin remodeling (Wright et al., 2016) and chromatin insulation (Yu et al., 2004, Ong et al., 97 2013), thereby organizing transcriptional regulation of distinct gene suites in response to cellular 98 signaling. However, it is unknown whether dopamine- or dopamine receptor-induced structural or 99 genomic changes are linked to PARP1/CTCF interaction. 100 In this study we demonstrate that dopamine receptor signaling generates pronounced 101 morphological changes in cultured astrocytes which
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