ChIP-seq of CTCF from mouse hippocampus. Mus musculus

CTCF is an organizer of higher-order chromatin structure, and regulates gene expression. Genetic studies have implicated mutations in CTCF in intellectual disabilities. However, there is no knowledge of the role of CTCF-mediated chromatin structure in learning and memory. We show that depletion of CTCF in postmitotic neurons, or depletion in the hippocampus of adult mice through viral-mediated knockout, induces deficits in learning and memory. These deficits in learning and memory at the beginning of adulthood are correlated with impaired long term potentiation and reduced spine density, with no changes in basal synaptic transmission and dendritic morphogenesis and arborization. Cognitive disabilities are associated with downregulation of cadherin and learning-related genes. In addition, CTCF knockdown attenuates fear conditioning-induced hippocampal gene expression of key learning genes and loss of long-range interactions at the BDNF and Arc loci. This study identifies CTCF-dependent gene expression regulation and DNA structure as regulators of learning and memory. Overall design: 2 biological replicates of mice and one input sample

CCCTC结合因子（CTCF）是高阶染色质结构（higher-order chromatin structure）的组织者，并可调控基因表达（gene expression）。遗传学研究表明，CTCF突变与智力障碍（intellectual disabilities）相关，但目前学界对CTCF介导的染色质结构在学习记忆（learning and memory）中的作用尚未明晰。本研究发现，在有丝分裂后神经元（postmitotic neurons）中耗竭CTCF，或通过病毒介导的基因敲除（viral-mediated knockout）在成年小鼠海马体（hippocampus）中耗竭CTCF，均可导致学习记忆功能缺陷。成年初期出现的此类学习记忆缺陷，与长时程增强（long-term potentiation）受损、树突棘密度（spine density）降低显著相关，且基础突触传递（basal synaptic transmission）、树突形态发生（dendritic morphogenesis）及树突分支（arborization）均未出现异常。认知障碍与钙粘蛋白（cadherin）及学习相关基因（learning-related genes）的下调存在关联。此外，CTCF敲低（CTCF knockdown）会削弱恐惧条件反射（fear conditioning）诱导的关键学习基因的海马基因表达，并破坏脑源性神经营养因子（BDNF, Brain-Derived Neurotrophic Factor）与活动调节细胞骨架蛋白（Arc, Activity-regulated cytoskeleton-associated protein）基因座（loci）的远程相互作用。本研究证实，CTCF依赖的基因表达调控与DNA结构是学习记忆的调控因子。整体实验设计：小鼠样本2个生物学重复，以及1个输入样本