Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239.
Cancer Early Detection Advanced Research Center, Oregon Health and Science Institute, Portland, Oregon 97239.
J Neurosci. 2021 Aug 4;41(31):6582-6595. doi: 10.1523/JNEUROSCI.2059-20.2021. Epub 2021 Jul 1.
Early studies in mouse neurodevelopment led to the discovery of the RE1 Silencing Transcription Factor (REST) and its role as a master repressor of neuronal gene expression. Recently, REST was reported to also repress neuronal genes in the human adult brain. These genes were found to be involved in pro-apoptotic pathways; and their repression, associated with increased REST levels during aging, were found to be neuroprotective and conserved across species. However, direct genome-wide REST binding profiles for REST in adult brain have not been identified for any species. Here, we apply this approach to mouse and human hippocampus. We find an expansion of REST binding sites in the human hippocampus that are lacking in both mouse hippocampus and other human non-neuronal cell types. The unique human REST binding sites are associated with genes involved in innate immunity processes and inflammation signaling which, on the basis of histology and recent public transcriptomic analyses, suggest that these new target genes are repressed in glia. We propose that the increases in REST expression in mid-adulthood presage the beginning of brain aging, and that human REST function has evolved to protect the longevity and function of both neurons and glia in human brain. The RE1 Silencing Transcription Factor (REST) repressor has served historically as a model for gene regulation during mouse neurogenesis. Recent studies of REST have also suggested a conserved role for REST repressor function across lower species during aging. However, direct genome-wide studies for REST have been lacking for human brain. Here, we perform the first genome-wide analysis of REST binding in both human and mouse hippocampus. The majority of REST-occupied genes in human hippocampus are distinct from those in mouse. Further, the REST-associated genes unique to human hippocampus represent a new set related to innate immunity and inflammation, where their gene dysregulation has been implicated in aging-related neuropathology, such as Alzheimer's disease.
早期的小鼠神经发育研究导致了 RE1 沉默转录因子（REST）的发现及其作为神经元基因表达主抑制因子的作用。最近，据报道 REST 也会抑制人类成年大脑中的神经元基因。这些基因被发现参与细胞凋亡途径；并且随着衰老过程中 REST 水平的升高，它们的抑制作用被发现具有神经保护作用，并且在物种间是保守的。然而，对于任何物种，尚未确定成年大脑中 REST 的全基因组 REST 结合谱。在这里，我们将这种方法应用于小鼠和人类海马体。我们发现人类海马体中 REST 结合位点的扩张在小鼠海马体和其他人类非神经元细胞类型中都不存在。独特的人类 REST 结合位点与先天免疫过程和炎症信号转导相关的基因相关，基于组织学和最近的公共转录组分析，表明这些新的靶基因在神经胶质中受到抑制。我们提出，成年中期 REST 表达的增加预示着大脑衰老的开始，并且人类 REST 功能已经进化为保护人类大脑中神经元和神经胶质的长寿和功能。RE1 沉默转录因子（REST）抑制剂在过去一直是小鼠神经发生过程中基因调控的模型。最近对 REST 的研究也表明，REST 抑制剂功能在较低物种的衰老过程中具有保守作用。然而，直接针对人类大脑的全基因组研究一直缺乏。在这里，我们首次对人类和小鼠海马体中的 REST 结合进行了全基因组分析。人类海马体中 REST 占据的大多数基因与小鼠中的不同。此外，人类海马体中独特的 REST 相关基因代表了一组与先天免疫和炎症相关的新基因，其基因失调与衰老相关的神经病理学有关，如阿尔茨海默病。
