Deciphering the cell type-specific gene regulatory network of learning

一个紧急的理解是，记忆的细胞相关性可能编码在表观遗传状态的改变中，受转录因子(TF)、染色质修饰物和重塑复合体的相互作用调节。尽管有证据表明染色质修饰参与了学习和记忆过程，以及几种认知障碍的病因，但很明显，我们目前只看到了冰山一角，因为像学习和记忆这样基本的东西的基因调控网络仍然远未被阐明。我们正在使用最先进的干湿实验室技术来获得体内短期和长期记忆形成背后的动态基因调控网络的第一张特定细胞类型的图片。我们的团队正在使用细胞类型特定的芯片-SEQ(BITS-CHIP)来阐明转录因子和染色质修饰物的协同作用如何调节负责记忆形成的基因及其调节元件的表观遗传状态，以及这种变化在老年痴呆或疾病中是如何变化的。关于特定大脑区域和细胞类型中的增强子、启动子和基因使用的详细信息将给予对学习和记忆潜在的调节状态及其在衰老和疾病中的变化的前所未有的洞察。综上所述，这些结果应该能够对疾病病因进行详细的洞察，并突出疾病预防或干预的潜在目标。

There is an emergent understanding that the cellular correlate of memory might be encoded in alterations of the epigenetic state, regulated by the interplay of transcription factors (TFs), chromatin modifiers and remodeling complexes. Despite evidence for the involvement of chromatin modifications in learning and memory processes and the etiology of several cognitive disorders, it is clear that we are currently only looking at the tip of the iceberg, as the gene regulatory network of something as fundamental as learning and memory is still far from being elucidated. We are using state of the art wet- and drylab technologies to get a first, cell type-specific picture of the dynamic gene regulatory network underlying short- and long-term memory formation in vivo. Our group is using cell type-specific ChIP-seq (BiTS-ChIP) to elucidate how the concerted action of transcription factors and chromatin modifiers regulate the epigenetic state of genes and their regulatory elements that are responsible for the formation of memory, and how this changes in senile dementia or disease.Detailed information on enhancer, promoter, and gene usage in specific brain areas and cell types will grant unprecedented insights into the regulatory state underlying learning and memory and its changes in aging and disease. Taken together, the results should permit detailed insights into disease etiology and highlight potential targets for disease prevention or intervention.