REST ChIP-seq in human and mouse hippocampus

The transcriptional repressor REST (RE1 Silencing Transcription Factor) is a master regulator of thousands of neuronal genes that together impart the terminally differentiated neuronal phenotype. Because of this unique feature, REST has been, and continues to be, a widely used model for understanding neurogenesis and neuronal cell function. These studies have focused primarily on murine embryonic development, but recent studies have pointed to distinct postnatal roles for REST in stroke, epilepsy, aging and cognitive decline. The function of REST in healthy human brain tissue, however, still remains poorly characterized. Here, we present deep sequencing chromatin immunoprecipitation evidence for divergent REST function in normal mouse and human postmortem adult hippocampus. In mouse, REST occupies only 221 peaks that are divided between prototypical REST target genes shared with non-neuronal cells, as well as peaks unique to the hippocampus. Surprisingly, the mouse hippocampal-unique sites are not conserved in human, which contains 1886 REST peaks unique to the hippocampus. Further, the REST peaks unique to the hippocampus represent a potentially new category of target genes encoding proteins important in the immune response. Our results suggest the possibility that REST protects against aberrant immunological responses during normal human aging and that mouse may not model this aging function.转录抑制因子REST（RE1 Silencing Transcription Factor，RE1沉默转录因子）是调控数千个神经元基因的核心调控因子，这些基因共同赋予细胞终末分化的神经元表型。凭借这一独特特性，REST过去是、至今仍是研究神经发生与神经元细胞功能的经典模型。过往相关研究多聚焦于小鼠胚胎发育过程，但近期研究揭示了REST在脑卒中、癫痫、衰老与认知衰退中发挥的独特出生后功能。然而，REST在健康成人脑组织中的功能仍未得到充分解析。本研究通过深度测序染色质免疫共沉淀技术，证实了正常小鼠与人类死后成人海马体中REST功能存在分化差异。在小鼠海马体中，REST仅结合221个染色质峰，这些峰可分为两类：一类是与非神经元细胞共享的典型REST靶基因结合位点，另一类是海马体特异性结合峰。令人意外的是，小鼠海马体特异性结合位点在人类中并不保守；人类海马体中存在1886个REST特异性结合峰。此外，人类海马体特异性REST结合峰所靶向的基因，属于一类潜在的新型靶基因家族，其编码的蛋白在免疫应答中发挥关键作用。本研究结果提示，REST或可在人类正常衰老过程中抵御异常免疫应答，而小鼠模型可能无法复现REST的这一衰老相关功能。