Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder that is associated with genetic risk factors. Most human disease-associated single-nucleotide polymorphisms (SNPs) are not located in genes but rather are in regulatory regions that control gene expression. The function of regulatory regions is determined through epigenetic mechanisms. Parallels between the cellular basis of development and the formation of long-term memory have long been recognized, particularly the role of epigenetic mechanisms in both processes. We analyzed how learning alters chromatin accessibility in the mouse hippocampus using a new high-throughput sequencing bioinformatics strategy we call DEScan (differential enrichment scan). DEScan, which enabled the analysis of data from epigenomic experiments containing multiple replicates, revealed changes in chromatin accessibility at 2365 regulatory regions—most of which were promoters. Learning-regulated promoters were active during forebrain development in mice and were enriched in epigenetic modifications indicative of bivalent promoters. These promoters were disproportionally intronic, showed a complex relationship with gene expression and alternative splicing during memory consolidation and retrieval, and were enriched in the data set relative to known ASD risk genes. Genotyping in a clinical cohort within one of these promoters (SHANK3 promoter 6) revealed that the SNP rs6010065 was associated with ASD. Our data support the idea that learning recapitulates development at the epigenetic level and demonstrate that behaviorally induced epigenetic changes in mice can highlight regulatory regions relevant to brain disorders in patients.

自闭症谱系障碍（ASD）是一种普遍的神经发育障碍，与遗传危险因素有关。大多数与人类疾病相关的单核苷酸多态性（SNP）都不位于基因中，而是位于控制基因表达的调节区域中。调节区域的功能是通过表观遗传机制确定的。长期以来，人们已经认识到细胞基础与长期记忆形成之间的平行关系，尤其是表观遗传机制在这两个过程中的作用。我们使用一种称为DEScan（差异富集扫描）的新型高通量测序生物信息学策略，分析了学习如何改变小鼠海马中的染色质可及性。DEScan，可以分析来自包含多个重复的表观基因组实验的数据，揭示了2365个调控区中染色质可及性的变化-其中大多数是启动子。受学习调节的启动子在小鼠前脑发育过程中是活跃的，并且富含指示二价启动子的表观遗传修饰。这些启动子是非比例内含子的，在记忆整合和检索过程中显示与基因表达和选择性剪接的复杂关系，并且相对于已知的ASD风险基因丰富了数据集。在这些启动子之一的临床队列中进行基因分型（在记忆整合和检索过程中显示出与基因表达和选择性剪接的复杂关系，并且相对于已知的ASD风险基因而言，其数据集中更为丰富。在这些启动子之一的临床队列中进行基因分型（在记忆整合和检索过程中显示出与基因表达和选择性剪接的复杂关系，并且相对于已知的ASD风险基因而言，其数据集中更为丰富。在这些启动子之一的临床队列中进行基因分型（SHANK3启动子6）揭示SNP rs6010065与ASD相关。我们的数据支持以下观点：学习在表观遗传水平上概括发展，并证明行为诱发的表观遗传变化可突出显示与患者脑部疾病相关的调节区域。