Department of Biomedical Sciences, Elson S. Floyd College of Medicine. Washington State University, Spokane, WA 99202, USA.
Ibis Biosciences Inc. of Abbot, Carlsbad, CA 92008, USA.
Sci Signal. 2018 Jan 16;11(513):eaan6500. doi: 10.1126/scisignal.aan6500.
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 ( 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）是一种常见的神经发育障碍，与遗传风险因素有关。大多数与人类疾病相关的单核苷酸多态性（SNP）不在基因中，而是在调节基因表达的调控区域。调控区域的功能是通过表观遗传机制来确定的。发育的细胞基础与长期记忆的形成之间的相似性早已被认识到，特别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）的新高通量测序生物信息学策略来分析学习如何改变小鼠海马体中的染色质可及性。DEScan 能够分析包含多个重复的表观基因组实验的数据，揭示了 2365 个调控区域的染色质可及性变化-其中大多数是启动子。学习调节的启动子在小鼠前脑发育过程中活跃，并且富含二价启动子的表观遗传修饰。这些启动子不成比例地位于内含子中，在记忆巩固和检索过程中与基因表达和选择性剪接之间存在复杂的关系，并且相对于已知的 ASD 风险基因在数据集中富集。对其中一个启动子（启动子 6）的临床队列进行基因分型显示，SNP rs6010065 与 ASD 相关。我们的数据支持学习在表观遗传水平上再现发育的观点，并表明小鼠的行为诱导的表观遗传变化可以突出与患者大脑疾病相关的调控区域。
