The Spatiotemporal Landscape of the Human Brain Epitranscriptome

人脑表观转录组的时空景观

基本信息

批准号：
9908172
负责人：
Christopher Edward Mason
金额：
$ 65.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908172
关键词：
Address Adenosine Adult Affect Alleles Alternative Splicing Atlases Autopsy Bioinformatics Biological Biological Assay Brain Brain Diseases Brain region CRISPR/Cas technology Cells Cerebellar Cortex Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Copy Number Polymorphism Cytosine DNA Methylation DNA Modification Process Data Data Set Development Disease susceptibility Environment Epigenetic Process Event Female Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Genotype-Tissue Expression Project Goals High-Throughput Nucleotide Sequencing Human Human Activities Institutes Knock-out Link Maps Mediating Mental disorders Modeling Modification Molecular Neuroglia Neurologic Neurons Patients Prefrontal Cortex Proteins Quantitative Trait Loci RNA RNA Editing RNA Splicing RNA methylation Reader Regulation Resources Sampling Site Somatosensory Cortex System Temporal Lobe Testing Time Tissue Banks Tissues Transcript Translations Untranslated RNA Variant Visualization area striata autism spectrum disorder autistic base bisulfite sequencing clinically relevant data resource epigenetic regulation epigenome epitranscriptome follow-up genome sequencing induced pluripotent stem cell inter-individual variation male methylome nervous system disorder neurodevelopment neuropsychiatric disorder postnatal postnatal development repository response risk variant spatiotemporal transcriptome translational medicine whole genome work-study

项目摘要

ABSTRACT The human Brainspan data was created to identify all transcripts involved in neural development and to help understand of how specific risk genes affect human brain development. In addition, these data will have important clinical relevance for translational medicine; these data can help discern which risk alleles associated with psychiatric and neurological disorders influence transcription and alternative splicing across different regions and developmental stages. Also, most Brainspan samples were processing for whole-genome sequencing (WGS) and/or DNA methylation analysis, which enables direct comparisons of single basepair changes, copy number variation, and RNA editing events in the developing human brain. As such, Brainspan data holds biologically and clinically important data on the genetic and molecular mechanisms underlying the development and increased disease susceptibility of the human brain. To expand upon this resource, we aim to create a matched profile of the human brains RNA modification landscape (epitranscriptome), for both methyl-6-adenosine (m6A) and 5-methyl-cytosine (5mC). We will profile the developmental trajectory of the RNA modifications and their activity in non-coding regions and impact on splicing, RNA editing, AU-rich regulation of transcripts, and association with DNA methylation changes (epigenetics). Finally, we will also test the impact of these modifications from patient-derived iPS cells that will be grown and assayed over five time points. This will be accomplished over five years, and across 1,075 samples, across the Mason and Sestan labs, with collaborators at the Broad institute available to help with assays and access to GTEx data from adult brains with m6A profiles. We will achieve these goals across three main aims. (1) Create a neuro-developmental map for epitranscriptome sites and levels, with an emphasis on m6A and m5C, for 35 brains from four time periods, and five regions of the brain, chosen based on their large differences seen in the BrainSpan data and prior implication in neurological development. (2) Detail the inter-individual variation in epitranscriptome levels and their epigenetic regulation using m6A variation with the changes in expression levels, and then link epigenetic changes to altered gene expression and m6A regulation. (3) We will delineate the epitranscriptome changes in autism brains and manifestation in patient-derived iPS cells, including an examination of epitranscriptome variation across 30 banked Autistic brain samples and testing of the impact on disruption of the readers and writers of RNA regulation (on induced pluripotent stem cells). These will represent the first-ever epitranscriptome maps from primary tissue of Autism brains and help guide future studies that examine the dysregulation of Autism gene expression networks and epitranscriptome states.

抽象的创建了人类脑盆腔数据，以识别与神经发育有关的所有成绩单和帮助了解特定风险基因如何影响人脑发育。此外，这些数据将具有转化医学的重要临床相关性；这些数据可以帮助辨别哪些风险等位基因相关随着精神病和神经系统疾病的影响，会影响不同的转录和替代剪接区域和发展阶段。此外，大多数脑锅样品正在处理全基因组测序（WGS）和/或DNA甲基化分析，可以直接比较单基台发展中大脑的变化，拷贝数变化和RNA编辑事件。因此，Brainspan 数据在生物学和临床上具有有关遗传和分子机制的重要数据人脑的发育和增加的疾病敏感性。为了扩展这种资源，我们旨在创建人类大脑RNA的匹配概况用于甲基-6-腺苷（M6A）和5-甲基 - 胞嘧啶（5MC）的修饰景观（表面参考）。我们将介绍RNA修饰的发育轨迹及其在非编码区域的活性对剪接，RNA编辑，富含转录本的调节以及与DNA甲基化的影响变化（表观遗传学）。最后，我们还将测试来自患者衍生的IPS细胞的这些修饰的影响这将在五个时间点上种植和测定。这将在五年内完成梅森和塞斯坦实验室的1,075个样品与广大研究所的合作者有帮助从具有M6A概况的成年大脑的测定和访问GTEX数据。我们将在三个主要目标中实现这些目标。（1）创建一个神经开发图表面参考组和级别，重点是M6A和M5C，在四个时期内进行了35个大脑，并且大脑的五个区域，根据它们在脑盆中数据中看到的巨大差异和先验选择对神经学发展的影响。（2）详细介绍表面翻译组水平的个体间变化他们使用M6A变异与表达水平变化的表观遗传调节，然后链接表观遗传学改变基因表达和M6A调节的变化。（3）我们将描绘出上映的变化自闭症的大脑和患者衍生的IPS细胞的表现，包括检查表演组 30种自闭症大脑样本的变化以及对读者中断的影响的测试 RNA调节的作者（在诱导多能干细胞上）。这些将代表有史以来的第一个来自自闭症大脑原发性组织的同意表图，并帮助指导未来的研究自闭症基因表达网络和表面参考组状态的失调。