Dynamic RNA Modifications in human brain development and autism

项目摘要 表观遗传调控在神经发育和神经精神疾病中起着关键作用 紊乱除了DNA和组蛋白修饰，还有150多个转录后修饰的 核糖核苷已在各种类型的RNA中被鉴定。此外，最近的研究表明， 转录后信使RNA（mRNA）修饰是动态调节的， 基因表达的结果。这些动态的RNA修饰代表了基因工程的一个关键的新领域。 RNA表观遗传学”或“表位转录组学”形式的表达调控。在不同的RNA之间 修改，我们已发表和未发表的工作表明，m6 A，m3 C和m1A是动态的，可以 在神经发育过程中发挥重要作用，如果 失调自闭症谱系障碍（ASD）是一组临床异质性发育障碍 经常表现为社会关系受损，语言和沟通受损， 兴趣范围和刻板行为。我们发现ASD相关基因受到广泛的影响， 人类大脑发育过程中的RNA修饰我们进一步开发了强大的技术， 在转录组水平上“定量”分析/绘制这些RNA特异性修饰的管道， 人类在这项拟议的PsychENCODE研究中，我们将使用死后组织和人类诱导多能 干细胞衍生的类器官系统地映射三种不同的mRNA/lncRNA修饰（m6 A，m3 C和 m1A），并确定未受影响的供体之间的任何差异模式 和ASD患者。这些数据集将为RNA标记如何影响全球生物多样性提供蓝图。 转录组，我们将注释对大脑发育重要的关键转录本的显著修改 和功能我们提出的工作将确定和功能注释epitranscriptome标记的关键后， 人类大脑发育和成年期的转录基因表达调控。一个系统 在人类大脑发育和ASD的背景下分析这些RNA修饰可以提供新的 对神经发育失调的脆弱性关键节点的功能性见解。

PROJECT SUMMARY Epigenetic regulation has been shown to play pivotal roles in neurodevelopmental and neuropsychiatric disorders. In addition to DNA and histone modifications, more than 150 post-transcriptionally modified ribonucleosides have been identified in various types of RNA. Furthermore, recent studies have suggested that post-transcriptional messenger RNA (mRNA) modifications are dynamically regulated and significantly impact the outcomes of gene expression. These dynamic RNA modifications represent a critical new realm for gene expression regulation in the form of “RNA epigenetics” or “Epitranscriptomics”. Among different RNA modifications, our published and unpublished works suggest that m6A, m3C and m1A are dynamic and could play important roles during neurodevelopment and, potentially, contribute to developmental pathology if dysregulated. Autism spectrum disorder (ASD) is a clinically heterogeneous group of developmental disorders frequently characterized by impaired social relationships, impaired language and communication, a limited range of interests and stereotypic behaviors. We have found that ASD-linked genes are subject to extensive RNA modifications during human brain development. We have further developed robust technologies and pipelines to “quantitatively” profile/map these RNA specific modifications at the transcriptome-wide level in humans. In this proposed PsychENCODE study, we will use postmortem tissue and human induced pluripotent stem cell-derived organoids to systematically map three distinct mRNA/lncRNA modifications (m6A, m3C and m1A) during normal human brain development and identify any differential patterns between unaffected donors and patients with ASD. These datasets will provide a blueprint of how RNA marks impact the global transcriptome and we will annotate prominent modifications on key transcripts important for brain development and function. Our proposed work will identify and functionally annotate epitranscriptome marks critical to post- transcriptional gene expression regulation across human brain development and adulthood. A systematic analysis of these RNA modifications in the context of human brain development and ASD could provide new functional insights into critical nodes of vulnerability for dysregulated neural development.