Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes
Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes
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DOI：
10.1523/jneurosci.3349-17.2018
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发表时间：
2018-05-23
影响因子：
5.3
通讯作者：
Ortinski, Pavel I.
中科院分区：
文献类型：
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作者：
Galloway, Ashley;Adeluyi, Adewale;Ortinski, Pavel I.
多巴胺在奖赏加工和药物成瘾的病因学中至关重要。整个大脑的星形胶质细胞表达多巴胺受体，但星形胶质细胞多巴胺受体信号传导的结果还没有很好地建立。我们发现，细胞外多巴胺触发快速浓度依赖性星座的星形胶质细胞的过程，这不是多巴胺氧化的结果，而是依赖于cAMP依赖性和cAMP非依赖性多巴胺受体信号。这伴随着星形胶质细胞钙瞬变的持续时间减少和频率增加，但对星形胶质细胞电压门控钾通道电流几乎没有影响。为了分离这些结构和功能变化的潜在机制，我们使用全基因组RNA测序，发现多巴胺诱导的含有CCCTC结合因子（CTCF）基序的基因显著富集，表明细胞核中染色质重组的参与。CTCF与启动子位点的结合双向调节基因转录，并依赖于聚ADP核糖聚合酶1（PARP1）的激活。因此，PARP1的拮抗作用阻断了多巴胺诱导的变化，而PARP1激动剂本身促进了多巴胺诱导的变化。这些结果表明，星形胶质细胞对多巴胺升高的反应涉及PARP1介导的CTCF基因组重组和基因网络的协调表达。我们的研究结果表明，染色质景观的表观遗传调控是星形胶质细胞对多巴胺快速反应的关键因素。
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 Ca2+ transients, but little effectonastrocytic voltage-gated potassium channel currents. Toisolate possible mechanisms underlying these structural and functional changes, we used whole-genomeRNAsequencing 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.