Papale Ligia A, Zhang Qi, Li Sisi, Chen Kailei, Keleş Sündüz, Alisch Reid S
Department of Psychiatry.
Department of Statistics, Biostatistics, and Medical Informatics and.
Hum Mol Genet. 2015 Dec 15;24(24):7121-31. doi: 10.1093/hmg/ddv411. Epub 2015 Sep 30.
The autism spectrum disorders (ASD) comprise a broad group of behaviorally related neurodevelopmental disorders affecting as many as 1 in 68 children. The hallmarks of ASD consist of impaired social and communication interactions, pronounced repetitive behaviors and restricted patterns of interests. Family, twin and epidemiological studies suggest a polygenetic and epistatic susceptibility model involving the interaction of many genes; however, the etiology of ASD is likely to be complex and include both epigenetic and environmental factors. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Here, we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate a genome-wide profile of striatal 5hmC in an autism mouse model (Cntnap2(-/-) mice) and found that at 9 weeks of age the Cntnap2(-/-) mice have a genome-wide disruption in 5hmC, primarily in genic regions and repetitive elements. Annotation of differentially hydroxymethylated regions (DhMRs) to genes revealed a significant overlap with known ASD genes (e.g. Nrxn1 and Reln) that carried an enrichment of neuronal ontological functions, including axonogenesis and neuron projection morphogenesis. Finally, sequence motif predictions identified associations with transcription factors that have a high correlation with important genes in neuronal developmental and functional pathways. Together, our data implicate a role for 5hmC-mediated epigenetic modulation in the pathogenesis of autism and represent a critical step toward understanding the genome-wide molecular consequence of the Cntnap2 mutation, which results in an autism-like phenotype.
自闭症谱系障碍（ASD）是一组广泛的与行为相关的神经发育障碍，每68名儿童中就有1人受其影响。ASD的特征包括社交和沟通互动受损、明显的重复行为以及兴趣模式受限。家族、双胞胎和流行病学研究表明，ASD存在一种多基因和上位性易感性模型，涉及许多基因的相互作用；然而，ASD的病因可能很复杂，包括表观遗传和环境因素。5-羟甲基胞嘧啶（5hmC）是一种新型的对环境敏感的DNA修饰，在有丝分裂后的神经元中高度富集，并且与神经元基因的活跃转录相关。在这里，我们使用一种成熟的化学标记和亲和纯化方法，结合高通量测序技术，在自闭症小鼠模型（Cntnap2(-/-)小鼠）中生成纹状体5hmC的全基因组图谱，发现9周龄的Cntnap2(-/-)小鼠在全基因组范围内5hmC发生破坏，主要发生在基因区域和重复元件中。将差异羟甲基化区域（DhMRs）注释到基因上，发现与已知的ASD基因（如Nrxn1和Reln）有显著重叠，这些基因富集了神经元本体功能，包括轴突发生和神经元投射形态发生。最后，序列基序预测确定了与转录因子的关联，这些转录因子与神经元发育和功能途径中的重要基因高度相关。总之，我们的数据表明5hmC介导的表观遗传调控在自闭症发病机制中起作用，并且代表了理解Cntnap2突变导致自闭症样表型的全基因组分子后果的关键一步。
