Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes

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 frequency of astrocytic Ca transients, but little effect on astrocytic voltage-gated potassium channel currents. To isolate possible mechanisms 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. Although dopamine is widely recognized for its role in modulating neuronal responses both in healthy and disease states, little is known about dopamine effects at non-neuronal cells in the brain. To address this gap, we performed whole-genome sequencing of astrocytes exposed to elevated extracellular dopamine and combined it with evaluation of effects on astrocyte morphology and function. We demonstrate a temporally dynamic pattern of genomic plasticity that triggers pronounced changes in astrocyte morphology and function. We further show that this plasticity depends on activation of genes sensitive to DNA-binding protein CTCF. Our results propose that a broad pattern of astrocyte responses to dopamine specifically relies on CTCF-dependent gene networks.

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

“…PARP1 modulates the function of the CCCTC-binding factor (CTCF) [321,322] and feeding behavior [323] in a circadian transcription-dependent manner [311,324]. Consistently, dopamine activates the PARP1/CTCFregulated transcriptional network to trigger morphological remodeling in astrocytes [325]. PARP1 is not only a potent modulator of SIRTuin activity [326] but also protects against genotoxic stress [315,327,328], optimizes efficient DNA repair [303], and facilitates longterm memory formation [329][330][331][332] and neuronal survival under stress [333][334][335].…”

Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders

“…22 A recent study demonstrated that GPR83 may play a role at the intersection of reward and learning as it was demonstrated that GPR83 expression is up-regulated in cultured hippocampal astrocytes following exposure to dopamine. 56 Finally, depletion of the long chain fatty acid docosahexaenoic acid, which results in a decrease in the rate of learning of an olfactory discrimination task, decreases GPR83 expression in the olfactory bulb. 57 These studies begin to highlight the variety of neurological functions wherein GPR83 may be playing a critical role, and which need to be explored further using mouse physiology and behavior.…”

Nicotinamide Augments the Anti-Inflammatory Properties of Resveratrol through PARP1 Activation

“…These two studies 21,22 thus suggest that PARP1 and PDE4 act in tandem to exert the metabolic benefits of resveratrol. Because both PARP1 and SIRTuins use NAD + , they antagonistically regulate each other, i.e; PARP1 activation inhibits SIRTuins through generation of nicotinamide 22,27,28 and vice versa the metabolic byproducts of nicotinamide (1-Methylnicotinamide) 29,30 or treatment with nicotinamide riboside (NR) result in the inhibition of PARP1 28,30 through SIRT1 activation 28,29,31 . Most significantly, inhibition of PARP1 leads to induction of DNA damage and cytotoxicity 32,33 and mitochondrial dysfunction 34 , which are implicated in the etiology of various metabolic disorders.…”

“…This leads us to hypothesize that the anti-inflammatory effects of RSV can be mimicked and enhanced upon treatment with NAM. Also known as niacinamide, NAM is a form of vitamin B3 and acts as a classical inhibitor of SIRT1 27,28 . In most mammalian cells, NAM is the main source of NAD + , which is necessary for cellular function and energy metabolism 44,45 .…”