Epigenetic determinants in oligodendrocyte maturation in Down Syndrome

唐氏综合症少突胶质细胞成熟的表观遗传决定因素

• 批准号: 10527889
• 负责人: Maria Medalla
• 金额: $ 45.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527889
• 关键词: 3-Dimensional; ATAC-seq; Adult; Affect; Architecture; Astrocytes; Axon; Biological Assay; Biology; Brain; Cell Line; Cell Nucleus; Cell model; Cells; Chromatin; Chromium; Chromosome 21; Chromosomes; Code; Cognition; DNA Methylation; Data; Deacetylation; Development; Disease; Down Syndrome; Electron Microscopy; Environment; Epigenetic Process; Failure; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genome; Global Change; Histone H3; Human; Human Chromosomes; Immunohistochemistry; Impairment; In Situ Hybridization; In Vitro; Individual; Intellectual functioning disability; Lead; Link; Lysine; Maintenance; Measures; Methods; Molecular; Molecular Target; Mus; Myelin; Neuraxis; Neurons; Oligodendroglia; Patients; Phenotype; Population; Process; Production; Regulatory Element; Resolution; Role; Shapes; Stains; Structure; Surveys; System; Testing; Transposase; Trisomy; Work; XCL1 gene; base; chromatin remodeling; confocal imaging; density; differential expression; epigenomics; experimental study; fetal; in vivo; induced pluripotent stem cell; mouse model; multimodality; myelination; nerve stem cell; neurotransmission; novel; novel therapeutic intervention; novel therapeutics; oligodendrocyte lineage; oligodendrocyte progenitor; programs; relating to nervous system; stem; stem cells; success; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Abstract Down Syndrome (DS) or trisomy 21 is caused by triplication of human chromosome 21 (HSA21), and it is the most common cause of intellectual disability. Triplication of HSA21 includes genes that are involved in cognition and brain function, as well as myelin production, and exerts global changes in the transcriptomic and epigenetic landscape in DS. Previous work on humans with DS and DS-mouse models have shown altered expression of myelin-related genes, as well as delayed OL maturation and disruption in myelin production, structure, and density. These changes, attributed partially to triplication of oligodendrocyte lineage transcription factors 1/2 (OLIG1/2), result in impaired myelination and abnormal neuronal conductivity, contributing to the intellectual deficits associated with DS. In addition to changes in the gene content caused by HSA21 triplication, there are well-recognized DS-related alterations of normal epigenetic landscape across the genome. These DS- related epigenetic changes can in turn influence myelination, because commitment and development of oligodendrocyte (OL) lineage is tightly regulated through the stage-dependent acquisition of repressive chromatin changes. In this project, we will provide the first examination of how changes in the epigenetic machinery alter OL biology in DS using human patient-derived induced pluripotent stem (iPS) cells. We will use a newly described 3D cellular model of OL spheroids (OLS) that contain oligodendrocyte, astrocyte, and neuronal populations, to provide a comprehensive, dynamic environment for studying myelination processes. Using this system, we will fully characterize changes in OL lineage commitment and development in human DS-derived isogenic lines and examine how these alterations are driven by changes in the epigenetic code regulating OL specification. Using fate- and differentiation-specific markers, we will fully characterize the generation and temporal development of OL lineage through the different maturational checkpoints, as well as the diversity of other constituent cell populations (including neurons and astrocytes) in trisomic and euploid OLS. Next, we will determine how the DS-associated epigenetic landscape shapes OL developmental and functional trajectory. We will reveal transcriptional dynamics and accessibility of chromatin in a variety of cellular populations developing within euploid and trisomic OLS using the Chromium Single Cell Multiome ATAC+Gene expression platform (10xGenomics), which combines RNA-seq and ATAC-seq profiling on the same population of cells. This will be the first study to directly link transcriptional changes in myelin-producing cells to the altered epigenomic circuitry in DS. Understanding the epigenetic mechanisms underlying the developmental vulnerability of these cells will point to novel therapeutic approaches that combine potential epidrugs and myelination-targeting approaches.

摘要 唐氏综合征（DS）或21三体是由人类21号染色体（HSA 21）的三倍引起的，它 是智力残疾最常见的原因。HSA 21的三倍体包括参与以下的基因： 认知和脑功能，以及髓鞘的产生，并在转录组和 表观遗传景观在DS。先前对患有DS的人类和DS小鼠模型的研究表明， 髓鞘相关基因的表达，以及延迟的OL成熟和髓鞘产生的破坏， 结构和密度。这些变化部分归因于少突胶质细胞谱系转录的三倍化 因子1/2（OLIG 1/2），导致髓鞘形成受损和神经元传导性异常，导致 与DS相关的智力缺陷。除了HSA 21三倍体引起的基因含量变化外， 在整个基因组中存在公认的正常表观遗传景观的DS相关改变。这些DS- 相关的表观遗传变化反过来又会影响髓鞘形成，因为髓鞘的形成和发育 少突胶质细胞（OL）谱系通过抑制性的阶段依赖性获得而受到严格调控。 染色质改变。 在这个项目中，我们将提供第一次检查如何改变表观遗传机制改变OL 使用人类患者来源的诱导多能干细胞（iPS）在DS中进行生物学研究。我们将使用一种新描述的 包含少突胶质细胞、星形胶质细胞和神经元群体的OL球状体（OLS）的3D细胞模型， 为研究髓鞘形成过程提供了一个全面、动态的环境。利用这个系统，我们将 充分表征人DS衍生的等基因系中OL谱系定型和发育的变化， 研究这些变化是如何驱动的表观遗传密码调节OL规格的变化。 使用命运和分化特异性标记，我们将充分表征世代和时间 通过不同的成熟检查点发展OL谱系，以及其他 三体和整倍体OLS中的组成细胞群（包括神经元和星形胶质细胞）。接下来我们就 确定DS相关的表观遗传景观如何塑造OL发育和功能轨迹。 我们将揭示转录动力学和可及性染色质在各种细胞群体 使用铬单细胞多组ATAC+基因表达在整倍体和三体OLS内发育 平台（10 xGenomics），其在相同细胞群体上组合了RNA-seq和ATAC-seq分析。 这将是第一项直接将髓鞘生成细胞中的转录变化与改变的神经细胞中的转录水平联系起来的研究。 DS中的表观基因组电路。了解发育的表观遗传机制 这些细胞的脆弱性将指出新的治疗方法，结合联合收割机潜在的地毯， 髓鞘化靶向方法。