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.

抽象的 唐氏综合症（DS）或三体疾病是由人类染色体21（HSA21）的一式陈述引起的，它是 是智力残疾的最常见原因。 HSA21的三分一式化包括涉及的基因 认知和大脑功能以及髓磷脂的产生，并在转录组和 DS中的表观遗传景观。以前关于DS和D​​S-Mouse模型的人类的工作已显示已改变 髓磷脂相关基因的表达，以及髓磷脂产生中的OL成熟和破坏的表达， 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一式三份 因子1/2（Olig1/2），导致髓鞘损害和神经元电导率异常，从而有助于 与DS相关的智力缺陷。除了由HSA21一式三份引起的基因含量变化外， 在整个基因组中，正常表观遗传景观有很好的认可DS相关的改变。这些DS- 相关的表观遗传变化反过来会影响髓鞘，因为承诺和发展 少突胶质细胞（OL）谱系通过阶段依赖的抑制作用严格调节 染色质改变。 在这个项目中，我们将首次检查表观遗传机制如何改变OL 使用人类衍生的诱导多能茎（IPS）细胞的DS生物学。我们将使用新描述的 含有少突胶质细胞，星形胶质细胞和神经元种群的OL球体（OLS）的3D细胞模型， 为研究髓鞘化过程提供了一个全面的动态环境。使用此系统，我们将 充分表征了人类DS衍生的同源线的OL谱系承诺和发展的变化， 检查这些改变是如何由调节OL规范的表观遗传密码变化驱动的。 使用命运和分化特异性标记，我们将充分表征生成和时间 通过不同的成熟检查点以及其他多样性的多样性开发OL谱系 trisomic和euploid OL中的组成细胞群（包括神经元和星形胶质细胞）。接下来，我们会的 确定与DS相关的表观遗传景观如何塑造OL发育和功能轨迹。 我们将揭示各种细胞种群中染色质的转录动力和可及性 使用Chromium单细胞MultioMe ATAC+基因表达在素中和三化OLS内发育 平台（10x基因组），将RNA-Seq和ATAC-Seq分析结合在相同的细胞群体上。 这将是第一项直接将产生髓磷脂细胞转录变化与已改变的转录变化联系起来的研究 DS中的表观基因组电路。了解发展的表观遗传机制 这些细胞的脆弱性将指出新型的治疗方法，这些方法结合了潜在的表育体和 髓鞘化靶向方法。