Dopamine triggers CTCF-dependent morphological and genomic remodeling of astrocytes

Ashley Galloway, Adewale Adeluyi, Bernadette O’donovan, Miranda L. Fisher, Chintada Nageswara Rao, Peyton Critchfield, Mathew Sajish, Jill R. Turner, Pavel I. Ortinski

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. We found that extracellular dopamine triggered rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. This was accompanied by reduced duration and increased frequencyof astrocyticCa2 transients, but littleeffect onastrocyticvoltage-gatedpotassiumchannel currents. Toisolatepossiblemechanisms underlying these structural and functional changes, we used whole-genome RNA sequencing and found prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) motif, suggesting involvement of chromatin restructuring in the nucleus. CTCF binding to promoter sites bidirectionally regulates gene transcription and depends on activation of poly-ADP-ribose polymerase 1 (PARP1). Accordingly, antagonism of PARP1 occluded dopamine-induced changes, whereas a PARP1 agonist facilitated dopamine-induced changes on its own. These results indicate that astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring and concerted expression of gene networks. Our findings propose epigenetic regulation of chromatin landscape as a critical factor in the rapid astrocyte response to dopamine.

Original languageEnglish
Pages (from-to)4846-4858
Number of pages13
JournalJournal of Neuroscience
Volume38
Issue number21
DOIs
StatePublished - May 23 2018

Bibliographical note

Publisher Copyright:
© 2018 the authors.

Keywords

  • Astrocyte
  • CTCF
  • Chromatin
  • Dopamine
  • PARP1
  • RNA sequencing

ASJC Scopus subject areas

  • General Neuroscience

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