TY - JOUR
T1 - Dopamine triggers CTCF-dependent morphological and genomic remodeling of astrocytes
AU - Galloway, Ashley
AU - Adeluyi, Adewale
AU - O’donovan, Bernadette
AU - Fisher, Miranda L.
AU - Rao, Chintada Nageswara
AU - Critchfield, Peyton
AU - Sajish, Mathew
AU - Turner, Jill R.
AU - Ortinski, Pavel I.
N1 - Publisher Copyright:
© 2018 the authors.
PY - 2018/5/23
Y1 - 2018/5/23
N2 - 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.
AB - 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.
KW - Astrocyte
KW - CTCF
KW - Chromatin
KW - Dopamine
KW - PARP1
KW - RNA sequencing
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UR - http://www.scopus.com/inward/citedby.url?scp=85050940824&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3349-17.2018
DO - 10.1523/JNEUROSCI.3349-17.2018
M3 - Article
C2 - 29712779
AN - SCOPUS:85050940824
SN - 0270-6474
VL - 38
SP - 4846
EP - 4858
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 21
ER -