Hung Holly A, Sun Guannan, Keles Sunduz, Svaren John
From the Waisman Center, Cellular and Molecular Pathology Graduate Program, and.
Departments of Biostatistics and Medical Informatics and.
J Biol Chem. 2015 Mar 13;290(11):6937-50. doi: 10.1074/jbc.M114.622878. Epub 2015 Jan 22.
Myelination of the peripheral nervous system is required for axonal function and long term stability. After peripheral nerve injury, Schwann cells transition from axon myelination to a demyelinated state that supports neuronal survival and ultimately remyelination of axons. Reprogramming of gene expression patterns during development and injury responses is shaped by the actions of distal regulatory elements that integrate the actions of multiple transcription factors. We used ChIP-seq to measure changes in histone H3K27 acetylation, a mark of active enhancers, to identify enhancers in myelinating rat peripheral nerve and their dynamics after demyelinating nerve injury. Analysis of injury-induced enhancers identified enriched motifs for c-Jun, a transcription factor required for Schwann cells to support nerve regeneration. We identify a c-Jun-bound enhancer in the gene for Runx2, a transcription factor induced after nerve injury, and we show that Runx2 is required for activation of other induced genes. In contrast, enhancers that lose H3K27ac after nerve injury are enriched for binding sites of the Sox10 and early growth response 2 (Egr2/Krox20) transcription factors, which are critical determinants of Schwann cell differentiation. Egr2 expression is lost after nerve injury, and many Egr2-binding sites lose H3K27ac after nerve injury. However, the majority of Egr2-bound enhancers retain H3K27ac, indicating that other transcription factors maintain active enhancer status after nerve injury. The global epigenomic changes in H3K27ac deposition pinpoint dynamic changes in enhancers that mediate the effects of transcription factors that control Schwann cell myelination and peripheral nervous system responses to nerve injury.
外周神经系统的髓鞘形成对于轴突功能和长期稳定性至关重要。外周神经损伤后，施万细胞从轴突髓鞘形成状态转变为脱髓鞘状态，这种状态支持神经元存活并最终实现轴突的重新髓鞘化。发育过程和损伤反应期间基因表达模式的重编程受到整合多种转录因子作用的远端调控元件的影响。我们使用染色质免疫沉淀测序（ChIP-seq）来测量组蛋白H3K27乙酰化（一种活性增强子的标记）的变化，以鉴定正在髓鞘化的大鼠外周神经中的增强子及其在脱髓鞘神经损伤后的动态变化。对损伤诱导的增强子的分析确定了c-Jun的富集基序，c-Jun是施万细胞支持神经再生所需的转录因子。我们在Runx2基因中鉴定出一个与c-Jun结合的增强子（Runx2是神经损伤后诱导产生的转录因子），并且我们表明Runx2是激活其他诱导基因所必需的。相比之下，神经损伤后失去H3K27ac的增强子富含Sox10和早期生长反应2（Egr2/Krox20）转录因子的结合位点这些转录因子是施万细胞分化的关键决定因素。神经损伤后Egr2表达丧失，并且许多Egr2结合位点在神经损伤后失去H3K27ac。然而，大多数与Egr2结合的增强子保留H3K27ac，这表明其他转录因子在神经损伤后维持活性增强子状态。H3K27ac沉积的整体表观基因组变化精确指出了增强子的动态变化，这些变化介导了控制施万细胞髓鞘形成和外周神经系统对神经损伤反应的转录因子的作用。
