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首页> 外文期刊>The EMBO journal. >PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure
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PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure

机译：PP4-dependent HDAC3脱磷酸作用轴突再生和之间的歧视再生失败

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摘要

The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small-molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
机译：的分子机制之间的差别再生失败与成功仍然是难以捉摸的。而regeneration-competent周围神经受伤坐骑再生基因表达反应在双相背根神经节(DRG)regeneration-incompetent感觉神经元中央脊髓损伤不。叉状分枝的响应提供了一个独特的机会探讨基本的生物机制支撑再生能力。药理屏幕小分子抑制剂针对关键表观遗传酶在DRG神经元,我们确认HDAC3候选人制动信号作为一个小说轴突再生的增长。确定再生外围但不是一个中央脊髓损伤引起的增加钙,而钙激活的蛋白质这反过来又脱去磷酸磷酸酶4HDAC3,从而削弱其活动和加强组蛋白乙酰化作用。体外H3K9ac ChIPseq和RNAseq打钻其次是启动子乙酰化作用和蛋白质研究涉及HDAC3表达式调节多种再生途径。最后,基因或药理HDAC3抑制了再生的失败脊髓损伤后感觉轴突。总之,这些数据表明PP4-dependentHDAC3脱磷酸作用之间的歧视轴突再生和再生失败。

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