Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo.
Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo.
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DOI：
10.1016/j.nepig.2016.10.002
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发表时间：
2016-12
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成人中枢神经系统（CNS）的轴突再生部分受到损伤神经元重新表达所需再生相关基因（RAG）的能力发育下降的限制。成年中枢神经系统神经元可能缺乏适当的促再生转录因子，或者可能表现出限制转录进入 RAG 的染色质结构。在这里，我们对关键 RAG 的启动子区域进行了表观遗传分析，发现了皮质成熟过程中的渐进限制。这些数据确定了成人中枢神经系统神经元轴突生长的潜在内在限制。然而，事实证明，培养的出生后皮质神经元的神经突生长对改善其他细胞类型轴突生长的治疗不敏感，包括 AP1 因子的组合过度表达、组蛋白乙酰转移酶的过度表达和组蛋白脱乙酰酶的药理学抑制剂。这种不敏感性可能是由于培养时染色质的中间闭合造成的，并凸显了用于测试潜在的促再生干预的细胞培养模型的重要差异。
Axon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the ability of injured neurons to re-express needed regeneration associated genes (RAGs). Adult CNS neurons may lack appropriate pro-regenerative transcription factors, or may display chromatin structure that restricts transcriptional access to RAGs. Here we performed epigenetic profiling around the promoter regions of key RAGs, and found progressive restriction across a time course of cortical maturation. These data identify a potential intrinsic constraint to axon growth in adult CNS neurons. Neurite outgrowth from cultured postnatal cortical neurons, however, proved insensitive to treatments that improve axon growth in other cell types, including combinatorial overexpression of AP1 factors, overexpression of histone acetyltransferases, and pharmacological inhibitors of histone deacetylases. This insensitivity could be due to intermediate chromatin closure at the time of culture, and highlights important differences in cell culture models used to test potential pro-regenerative interventions.