The Spatiotemporal Landscape of the Human Brain Epitranscriptome

人脑表观转录组的时空景观

• 批准号: 10378056
• 负责人: Christopher Edward Mason
• 金额: $ 64.94万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378056
• 关键词: ASD patient; Address; Adenosine; Adult; Affect; Alleles; Alternative Splicing; Atlases; Autopsy; Bioinformatics; 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

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。

项目成果

The COVID-19 XPRIZE and the need for scalable, fast, and widespread testing.

• DOI: 10.1038/s41587-020-0655-4
• 发表时间: 2020-09
• 期刊: Nature biotechnology
• 影响因子: 46.9
• 作者: MacKay MJ;Hooker AC;Afshinnekoo E;Salit M;Kelly J;Feldstein JV;Haft N;Schenkel D;Nambi S;Cai Y;Zhang F;Church G;Dai J;Wang CL;Levy S;Huber J;Ji HP;Kriegel A;Wyllie AL;Mason CE
• 通讯作者: Mason CE

Spatial omics technologies at multimodal and single cell/subcellular level.

• DOI: 10.1186/s13059-022-02824-6
• 发表时间: 2022-12-13
• 期刊: Genome biology
• 影响因子: 12.3

Circulating miRNA Spaceflight Signature Reveals Targets for Countermeasure Development.

• DOI: 10.1016/j.celrep.2020.108448
• 发表时间: 2020-12-08
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Malkani S;Chin CR;Cekanaviciute E;Mortreux M;Okinula H;Tarbier M;Schreurs AS;Shirazi-Fard Y;Tahimic CGT;Rodriguez DN;Sexton BS;Butler D;Verma A;Bezdan D;Durmaz C;MacKay M;Melnick A;Meydan C;Li S;Garrett-Bakelman F;Fromm B;Afshinnekoo E;Langhorst BW;Dimalanta ET;Cheng-Campbell M;Blaber E;Schisler JC;Vanderburg C;Friedländer MR;McDonald JT;Costes SV;Rutkove S;Grabham P;Mason CE;Beheshti A
• 通讯作者: Beheshti A

Holobiont Urbanism: sampling urban beehives reveals cities' metagenomes.

• DOI: 10.1186/s40793-023-00467-z
• 发表时间: 2023-03-30
• 期刊: Environmental microbiome
• 影响因子: 7.9

Haplotype diversity and sequence heterogeneity of human telomeres.

• DOI: 10.1101/gr.274639.120
• 发表时间: 2021-07
• 期刊: Genome research
• 影响因子: 7
• 作者: Grigorev K;Foox J;Bezdan D;Butler D;Luxton JJ;Reed J;McKenna MJ;Taylor L;George KA;Meydan C;Bailey SM;Mason CE
• 通讯作者: Mason CE