Shulha Hennady P, Cheung Iris, Whittle Catheryne, Wang Jie, Virgil Daniel, Lin Cong L, Guo Yin, Lessard Andree, Akbarian Schahram, Weng Zhiping
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Arch Gen Psychiatry. 2012 Mar;69(3):314-24. doi: 10.1001/archgenpsychiatry.2011.151. Epub 2011 Nov 7.
Neuronal dysfunction in cerebral cortex and other brain regions could contribute to the cognitive and behavioral defects in autism.
To characterize epigenetic signatures of autism in prefrontal cortex neurons.
We performed fluorescence-activated sorting and separation of neuronal and nonneuronal nuclei from postmortem prefrontal cortex, digested the chromatin with micrococcal nuclease, and deeply sequenced the DNA from the mononucleosomes with trimethylated H3K4 (H3K4me3), a histone mark associated with transcriptional regulation. Approximately 15 billion base pairs of H3K4me3-enriched sequences were collected from 32 brains.
Academic medical center.
A total of 16 subjects diagnosed as having autism and 16 control subjects ranging in age from 0.5 to 70 years.
Identification of genomic loci showing autism-associated H3K4me3 changes in prefrontal cortex neurons.
Subjects with autism showed no evidence for generalized disruption of the developmentally regulated remodeling of the H3K4me3 landscape that defines normal prefrontal cortex neurons in early infancy. However, excess spreading of H3K4me3 from the transcription start sites into downstream gene bodies and upstream promoters was observed specifically in neuronal chromatin from 4 of 16 autism cases but not in controls. Variable subsets of autism cases exhibit altered H3K4me3 peaks at numerous genes regulating neuronal connectivity, social behaviors, and cognition, often in conjunction with altered expression of the corresponding transcripts. Autism-associated H3K4me3 peaks were significantly enriched in genes and loci implicated in neurodevelopmental diseases.
Prefrontal cortex neurons from subjects with autism show changes in chromatin structures at hundreds of loci genome-wide, revealing considerable overlap between genetic and epigenetic risk maps of developmental brain disorders.
大脑皮层和其他脑区的神经元功能障碍可能导致自闭症患者出现认知和行为缺陷。
描述前额叶皮层神经元中自闭症的表观遗传特征。
我们对死后前额叶皮层的神经元和非神经元细胞核进行了荧光激活分选和分离，用微球菌核酸酶消化染色质，并用与转录调控相关的组蛋白标记三甲基化H3K4（H3K4me3）对单核小体中的DNA进行深度测序。从32个大脑中收集了约150亿碱基对的富含H3K4me3的序列。
学术医疗中心。
共有16名被诊断为自闭症的受试者和16名年龄在0.5至70岁之间的对照受试者。
鉴定在前额叶皮层神经元中显示出自闭症相关H3K4me3变化的基因组位点。
自闭症患者没有证据表明定义婴儿早期正常前额叶皮层神经元的H3K4me3景观的发育调控重塑受到普遍破坏。然而，在16例自闭症病例中的4例的神经元染色质中，特别观察到H3K4me3从转录起始位点过度扩散到下游基因体和上游启动子，但在对照组中未观察到。不同的自闭症病例亚组在许多调节神经元连接、社会行为和认知的基因处表现出改变的H3K4me3峰，通常与相应转录本的表达改变同时出现。自闭症相关的H3K4me3峰在与神经发育疾病相关的基因和位点中显著富集。
自闭症患者的前额叶皮层神经元在全基因组数百个位点处显示出染色质结构变化，揭示了发育性脑疾病的遗传和表观遗传风险图谱之间存在相当大的重叠。
