Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions
Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions
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DOI：
10.1093/hmg/ddh065
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发表时间：
2004-03-15
影响因子：
3.5
通讯作者：
Myers, RM
中科院分区：
文献类型：
--
作者：
Li, JZ;Vawter, MP;Myers, RM
研究精神或神经系统疾病中的基因表达异常通常涉及使用死后脑组织。与单细胞生物或克隆细胞系相比，人类受试者的生物环境和病史无法控制，并且通常难以完全记录。发现显著和可复制变化的机会取决于所研究对象之间观察到的变化的性质和幅度。在分析情绪障碍的基因表达变化过程中，我们观察到120个样本中存在显著程度的自然变异，这些样本代表了40名受试者的三个大脑区域。大多数这种多样性可以通过两种不同的表达模式来解释，这反过来又与组织pH值密切相关。长期处于濒死状态的个体，如呼吸骤停、多器官衰竭或昏迷，大脑中的pH值往往较低;而那些经历过短暂死亡的人，与事故，心脏病或窒息有关，一般具有正常的pH值。较低的pH值的样品表现出系统性的减少参与能量代谢和蛋白水解活性的基因的表达，和编码应激反应蛋白和转录因子的基因的一致增加。改变的基因的这种功能特异性表明，这种差异不仅仅是由于低pH样品中的随机RNA降解;相反，它反映了活细胞中广泛且积极协调的生物反应。这些发现揭示了在不同形式的终末应激期间参与的关键分子机制，并可能提示保护或恢复的临床目标。
Studies of gene expression abnormalities in psychiatric or neurological disorders often involve the use of postmortem brain tissue. Compared with single-cell organisms or clonal cell lines, the biological environment and medical history of human subjects cannot be controlled, and are often difficult to document fully. The chance of finding significant and replicable changes depends on the nature and magnitude of the observed variations among the studied subjects. During an analysis of gene expression changes in mood disorders, we observed a remarkable degree of natural variation among 120 samples, which represented three brain regions in 40 subjects. Most of such diversity can be accounted for by two distinct expression patterns, which in turn are strongly correlated with tissue pH. Individuals who suffered prolonged agonal states, such as with respiratory arrest, multi-organ failure or coma, tended to have lower pH in the brain; whereas those who experienced brief deaths, associated with accidents, cardiac events or asphyxia, generally had normal pH. The lower pH samples exhibited a systematic decrease in expression of genes involved in energy metabolism and proteolytic activities, and a consistent increase of genes encoding stress-response proteins and transcription factors. This functional specificity of changed genes suggests that the difference is not merely due to random RNA degradation in low pH samples; rather it reflects a broad and actively coordinated biological response in living cells. These findings shed light on critical molecular mechanisms that are engaged during different forms of terminal stress, and may suggest clinical targets of protection or restoration.