Methylomic and genomic impacts of organic pollutants in Dup15q syndrome

有机污染物对 Dup15q 综合征的甲基组学和基因组影响

基本信息

批准号：
8487405
负责人：
Janine M LaSalle
金额：
$ 33.86万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-12 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8487405
关键词：
15q Age Autistic Disorder Autopsy Behavioral Binding Proteins Bioinformatics Birth Brain Candidate Disease Gene Cell Culture Techniques Cell Differentiation process Cell Line Cells Child Chromatin Chromatin Loop Chromatin Structure Chromosomal Breaks Chromosomes Chromosomes, Human, Pair 15 Clinical Complex Copy Number Polymorphism DNA DNA Methylation DNA Sequence DNA Sequence Rearrangement Defect Development Disease Employee Strikes Environment Environmental Exposure Environmental Pollutants Environmental Risk Factor Epigenetic Process Etiology Exhibits Exposure to Flame Retardants Frequencies Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Risk Genome Genome Stability Genomic Instability Genomics Goals Health Heterogeneity Human Human Cell Line Human Chromosomes Human Genome Lead Measurable Mediating Methyl-CpG-Binding Protein 2 Methylation Modeling Molecular Conformation Molecular Profiling Mus Mutation Neurodevelopmental Disorder Neurons Nicotinic Receptors Play Polychlorinated Biphenyls Prevention strategy Primates RNA Receptor Gene Repetitive Sequence Rett Syndrome Role Sampling Sequence Analysis Structure Syndrome System Technology Testing Toxic Environmental Substances Transcript Variant autism spectrum disorder base bisulfite brain tissue design epigenome epigenomics genome-wide improved methylome mouse model next generation sequencing novel novel diagnostics pentabromodiphenyl ether phenyl ether pollutant social synaptic function synaptogenesis treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This study is designed to test a novel paradigm that the human genome dynamically interacts with the environment and that epigenetic mechanisms are at the interface of genome- environment interactions. The human genome is marked by structural variations including large copy number variations and differences in repetitive sequences. Environmental toxins such as polychlorinated biphenyls (PCBs) can induce DNA hypomethylation. DNA hypomethylation is a known contributor to genomic instability of CpG-rich Alu repeats in the primate lineage. Chromosome 15q11-13 duplication syndrome (Dup15q), is the most common copy number variation observed in neurodevelopmental disorders, and is responsible for 1-3% of autism cases. This proposal is based on the serendipitous finding that human brain samples with Dup15q syndrome showed significantly higher levels of the persistent organic pollutant PCB-95 than controls or idiopathic autism cases. Furthermore, a genetically susceptible mouse perinatally exposed to the related flame retardant BDE-47 exhibited hypomethylation in brain and reduced sociability compared to controls. This study is designed to experimentally determine if PCB-95 and/or BDE-47 play a causal or compounding role in structural rearrangements of 15q using combined genomic and epigenomic approaches. In addition, this study will directly investigate the effect of combined genomic and environmental insults on the integrity of the methylome and transcriptome in human brain samples. The first aim seeks to experimentally model chromosome 15 duplication in a novel human cell line system to examine effects of PCB-95 or BDE-47 exposures on genomic stability (DNA-seq) and DNA methylation (MethylC-seq) using next generation sequencing technology. In the second aim, the effect of genetic and epigenetic changes on long-range chromatin loop structure within 15q11-q13 will be examined by chromatin conformation capture sequencing (4C-seq) and correlated to specific transcriptional alterations. The third aim seeks to directly investigate specific 15q gene targets for epigenetic and transcriptional changes in human brain samples with and without chromosome 15 duplication and high PCB-95 levels. The results of these studies are expected to formally test the hypothesis that DNA methylation levels reduced by specific environmental pollutants may result in genomic rearrangements and alterations in long-range chromatin, leading to transcriptional changes. In addition, epigenetic alterations of autism candidate genes involved in synaptogenesis in human brain samples are expected to be uncovered by this approach. Finally, the results of these studies are expected to be broadly relevant to understanding the relationship between the genome, environmental exposures, and the epigenome in human health and disease.

描述（由申请人提供）：本研究旨在测试人类基因组与环境动态相互作用的新型范式，并且表观遗传机制位于基因组环境相互作用的界面。人基因组的结构变化为标志，包括大拷贝数变化和重复序列的差异。环境毒素，例如多氯联苯（PCB）可以诱导DNA低甲基化。 DNA低甲基化是灵长类动物谱系中富含CpG的ALU重复重复基因组不稳定性的已知贡献者。 15q11-13染色体复制综合征（DUP15Q）是在神经发育障碍中观察到的最常见的拷贝数变化，并导致1-3％的自闭症病例。该提案基于偶然发现，即患有DUP15Q综合征的人脑样品显示出持续性有机污染物PCB-95的水平明显高于对照或特发性自闭症病例。此外，与对照组相比，暴露于相关的阻燃BDE-47的遗传易感小鼠围产期暴露于相关的阻燃BDE-47中表现出低甲基化，社交性降低。这项研究旨在通过实验确定PCB-95和/或BDE-47是否使用合并的基因组和表观基因组方法在15Q的结构重排中起因果或复合作用。此外，这项研究将直接研究基因组和环境损伤对人脑样品中甲基甲基和转录组完整性的影响。第一个目的旨在在新型的人类细胞系系统中对15染色体进行实验模型，以检查PCB-95或BDE-47暴露对基因组稳定性（DNA-SEQ）和DNA甲基化（甲基C-SEQ）的影响，使用下一代测序技术。在第二个目标中，将通过染色质构象捕获测序（4C-Seq）来检查遗传和表观遗传变化对远程染色质环结构的影响，并与特定的转录改变相关。第三个目的旨在直接研究具有和没有染色体15染色体重复和高PCB-95水平的人脑样品的表观遗传和转录变化的特定15Q基因靶标。预计这些研究的结果将正式检验以下假设：特定环境污染物降低的DNA甲基化水平可能导致基因组重排和远程染色质的改变，从而导致转录变化。此外，这种方法预计将发现与人脑样本突触发生的自闭症候选基因的表观遗传改变。最后，这些研究的结果预计将与了解人类健康和疾病中的基因组，环境暴露和表观基因组之间的关系广泛相关。