Determining the neurodevelopmental cell type specific regulatory networks impacted in Down syndrome

摘要 资助父母基金摘要：唐氏综合症是人类最常见的遗传疾病， 智力残疾的主要原因。尽管Down的表型严重程度和程度 综合征的部分原因是21号染色体的额外拷贝，关于生物机制的细节 以及非典型发展的出现是不被理解的。为了解决这一重大的知识差距， 此前，我们使用单细胞RNA测序技术制作了一份《唐氏综合症发育细胞图谱》 分析来自多个组织的超过700,000个细胞的转录本。这项提案代表了我们的 正在进行的努力，以表征存在于细胞表型的分子和细胞特性 唐氏综合征患者的大脑发育。在目标1中，我们将唐氏综合征细胞映射到一个参考 通过汇集现有的单细胞RNA测序数据来构建发育中的人脑的框架。在目标2中，我们 将使用我们已建立的人类大脑功能基因组学流水线来推断特定细胞类型的基因调控 唐氏综合征患者的网络发生了改变。利用现有数据，这项研究将提供关于 唐氏综合征早期脑发育的出现和调节可用于阐明 早期神经病理基础的分子机制和相关疾病的基准模型系统 神经元表型。 请求补充材料摘要：本申请是根据以下规定提交的 不是-OD-21-076。这项研究补充的目的是从实验上验证我们细胞的发现- 利用高分辨率染色质作图进行类型特异性基因调控网络分析。我们建议使用 对照和21三体发育脑组织的单细胞染色质图谱。我们将整合这些新的 用我们现有的单核基因表达数据来证实预测的基因调控网络 通过我们的人脑功能基因组学管道。补充目标的成功完成将明确 基因调控网络在唐氏综合征脑发育中受到干扰，并构成未来的基础 旨在阐明临床表型之前的细胞和分子后果的研究。

ABSTRACT Abstract of the funded parent grant: Down syndrome is the most prevalent genetic condition in humans and a major cause of intellectual disability. Although the severity and extent of phenotypes present in Down syndrome partially result from an extra copy of chromosome 21, details regarding the biological mechanisms and the emergence of atypical development are not understood. To address this significant gap in knowledge, we previously created a ‘Developmental Cell Atlas of Down Syndrome’ by using single-cell RNA-sequencing to profile the transcriptomes of over 700,000 cells derived from multiple tissues. This proposal represents our ongoing efforts to characterize the molecular and cellular identity of cellular phenotypes present in the developing brain in Down syndrome. In Aim 1, we will map the Down syndrome cells onto a reference framework of the developing human brain by pooling existing single-cell RNA-sequencing data. In Aim 2, we will use our established human brain functional genomics pipeline to infer cell-type-specific gene regulatory networks altered in Down syndrome. Leveraging existing data, this study will provide critical information about the emergence and regulation of early brain development in Down syndrome that can be used to elucidate the molecular mechanisms underlying early neuropathology and to benchmark model systems for disease relevant neuronal phenotypes. Abstract of the requested supplement: This application is being submitted for PA-20-272 in accordance with NOT-OD-21-076. The goal of this research supplement is to experimentally validate the findings from our cell- type specific gene regulatory network analysis using high resolution chromatin mapping. We propose to use single cell chromatin mapping in control and trisomy 21 developing brain tissue. We will integrate these new data with our existing single-nucleus gene expression data to confirm the gene regulatory networks predicted via our human brain functional genomics pipeline. Successful completion of the supplementary aims will define gene regulatory networks that are perturbed in Down syndrome brain development and form the basis of future studies aimed at elucidating the cellular and molecular consequences that precede clinical phenotypes.