Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice.
Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice.
复制标题
神经元特异性 SUMO 敲低可抑制小鼠短暂前脑缺血后的整体基因表达反应，并使功能结果恶化。
DOI：
10.1016/j.neuroscience.2016.11.036
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发表时间：
2017-02-20
期刊：
影响因子：
3.3
通讯作者：
Yang W
中科院分区：
文献类型：
--
作者：
Zhang L;Liu X;Sheng H;Liu S;Li Y;Zhao JQ;Warner DS;Paschen W;Yang W
小泛素样修饰物（SUMO）缀合（SUMO化）在健康和疾病的神经功能中起着关键作用。神经元SUMO化对于情绪和认知是必不可少的，并且该途径在缺血后神经元中被显著激活，这是对缺血的神经保护反应。从细胞培养研究中也知道SUMO化调节基因表达。然而，它仍然是未知的SUMO化如何调节神经元基因表达在体内，在生理状态和缺血后，并调节缺血后神经功能的恢复。为了解决这些重要的问题，我们使用了SUMO 1 -3敲低（SUMO-KD）小鼠，其中Thy-1启动子驱动针对SUMO 1 -3的3种不同microRNA的表达，以特异性沉默神经元中的SUMO表达。使野生型和SUMO-KD小鼠经受短暂前脑缺血。在海马CA 1区样本中进行微阵列分析，并评估神经功能。SUMO化对缺血前后神经元基因表达的影响相反。在生理状态下，与野生型小鼠相比，SUMO-KD中大多数受SUMO化调控的基因上调。脑缺血/再灌注显著调节了野生型小鼠中400多个基因的表达水平，其中大多数基因上调。这种缺血后转录组变化的程度在SUMO-KD小鼠中受到抑制。此外，SUMO-KD小鼠表现出明显较差的功能结果。这表明，由于SUMO敲低而导致的缺血后脑中的整体基因表达反应的抑制对缺血后神经功能具有负面影响。总之，我们的数据为未来的研究提供了基础，以机械地将SUMO化与健康和疾病中的神经功能联系起来。
Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) plays key roles in neurologic function in health and disease. Neuronal SUMOylation is essential for emotionality and cognition, and this pathway is dramatically activated in post-ischemic neurons, a neuroprotective response to ischemia. It is also known from cell culture studies that SUMOylation modulates gene expression. However, it remains unknown how SUMOylation regulates neuronal gene expression in vivo, in the physiologic state and after ischemia, and modulates post-ischemic recovery of neurologic function. To address these important questions, we used a SUMO1-3 knockdown (SUMO-KD) mouse in which a Thy-1 promoter drives expression of 3 distinct microRNAs against SUMO1-3 to silence SUMO expression specifically in neurons. Wild-type and SUMO-KD mice were subjected to transient forebrain ischemia. Microarray analysis was performed in hippocampal CA1 samples, and neurologic function was evaluated. SUMOylation had opposite effects on neuronal gene expression before and after ischemia. In the physiological state, most genes regulated by SUMOylation were up-regulated in SUMO-KD compared to wild-type mice. Brain ischemia/reperfusion significantly modulated the expression levels of more than 400 genes in wild-type mice, with a majority of those genes upregulated. The extent of this post-ischemic transcriptome change was suppressed in SUMO-KD mice. Moreover, SUMO-KD mice exhibited significantly worse functional outcome. This suggests that suppression of global gene expression response in post-ischemic brain due to SUMO knockdown has a negative effect on post-ischemic neurologic function. Together, our data provide a basis for future studies to mechanistically link SUMOylation to neurologic function in health and disease.