PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system
PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system
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DOI：
10.1038/ncomms4527
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发表时间：
2014-04-01
影响因子：
16.6
通讯作者：
Di Giovanni, Simone
中科院分区：
文献类型：
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作者：
Puttagunta, Radhika;Tedeschi, Andrea;Di Giovanni, Simone
轴突再生衰竭是中枢神经系统（CNS）损伤后神经功能损害的主要原因，而不是周围神经系统（PNS）损伤。值得注意的是，PNS损伤触发了协调的再生基因表达程序。然而，逆行信号传导与导致差异再生能力的基因表达程序调控之间的分子联系仍然难以捉摸。在这里，我们通过系统的表观遗传学研究表明，在外周而非中枢轴索损伤后，组蛋白乙酰转移酶p300/ cbp相关因子（PCAF）在已建立的关键再生相关基因的启动子上促进组蛋白3lys 9的乙酰化。此外，我们发现细胞外信号调节激酶（ERK）介导的逆行信号是pcaf依赖性再生基因重编程所必需的。最后，PCAF是调节依赖性轴突再生所必需的，它也能促进脊髓损伤后的再生。因此，我们发现了调节中枢神经系统轴突再生的特定表观遗传机制，为临床应用提供了新的靶点。
Axonal regenerative failure is a major cause of neurological impairment following central nervous system (CNS) but not peripheral nervous system (PNS) injury. Notably, PNS injury triggers a coordinated regenerative gene expression programme. However, the molecular link between retrograde signalling and the regulation of this gene expression programme that leads to the differential regenerative capacity remains elusive. Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. Thus, we find a specific epigenetic mechanism that regulates axonal regeneration of CNS axons, suggesting novel targets for clinical application.