Epigenetic Regulation of the Maturation and Function of Lung Epithelium by the SWI/SNF Proteins ARID1A and ARID1B.

SWI/SNF 蛋白 ARID1A 和 ARID1B 对肺上皮成熟和功能的表观遗传调控。

• 批准号: 10178696
• 负责人: DANIEL, T (MD) Todd Swarr
• 金额: $ 35.78万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-20 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10178696
• 关键词: ARID1A gene; ATAC-seq; Address; Adult; Alveolar; Alveolar Cell; Alveolus; Binding; Biological Models; Birth; Bronchopulmonary Dysplasia; CRISPR interference; Cell Differentiation process; Cell Maturation; Cell division; Cell physiology; Chemicals; Chromatin; Chromatin Remodeling Factor; Chronic Obstructive Airway Disease; Chronic lung disease; Code; Cre driver; DNA Sequence; Data; Data Set; Development; Disease; Disease Progression; Distal; Doxycycline; Drosophila snf protein; Epigenetic Process; Epithelial; Epithelial Cells; Family member; Flow Cytometry; Foundations; Future; Gene Expression; Genes; Genetic Transcription; Histology; Homeostasis; Human; Impairment; Information Systems; Injury; LoxP-flanked allele; Lung; Lung diseases; Mediating; Mediator of activation protein; Molecular; Mus; Pathogenesis; Pathologic; Pattern; Perinatal; Play; Population; Process; Proliferating; Proteomics; Regulatory Element; Respiratory distress; Role; SHH gene; SWI/SNF Family Complex; Structure; System; Systems Biology; Therapeutic; Time; Work; alveolar epithelium; base; cell type; chromatin remodeling; epigenetic regulation; epigenome; epigenomics; epithelial repair; epithelial stem cell; epithelium regeneration; genetic information; genome-wide; human pluripotent stem cell; influenza infection; injury and repair; lung development; lung injury; lung regeneration; lung repair; neonatal death; postnatal; programs; pulmonary function; repaired; response; response to injury; stem; stem cells; surfactant; targeted treatment; tool; transcription factor; transcriptome sequencing; transcriptomics; translational study

PROJECT SUMMARY: It is being increasingly recognized that changes in chromatin state are associated with a wide spectrum of lung diseases, ranging from bronchopulmonary dysplasia (BPD) to chronic obstructive pulmonary disease (COPD). However, the mechanisms by which these changes contribute to the pathogenesis of these diseases, and how to manipulate the epigenome for therapeutic benefit, remains largely unknown. Modulation of chromatin accessibility is an important epigenetic mechanism by which gene expression is controlled, even across repeated cell divisions. However, as a prerequisite to understanding how altered chromatin accessibility contributes to disease, the mechanisms by which chromatin accessibility patterns first establish and maintain cellular identity within the lung must be defined. This proposal is based on studies from our group that identified the SWI/SNF proteins Arid1a and Arid1b as key mediators of the chromatin accessibility changes that occur during development of the SOX9+ lung epithelial stem/progenitor cell population. Our data demonstrate that loss of Arid1a or Arid1b led to persistence of the SOX9+ progenitor cell population, impaired alveolar differentiation, and neonatal death due to respiratory distress. In addition, ARID1A directly interacts with NKX2-1 and SOX9. The central hypothesis of the present proposal is that ARID1A and ARID1B interact with key lung developmental TFs to direct the SWI/SNF complex to remodel chromatin at specific loci, silencing progenitor cell gene expression programs and promoting the maturation and function of the mature alveolar epithelium. The proposed studies will: A) Define the role that Arid1a/Arid1b, and the larger SWI/SNF complex, play in establishment of mature alveolar cell type identify in mouse and human. B) Identify the mechanism(s) by which the SWI/SNF complex remodels chromatin, in conjunction with key lung transcription factors, to establish and maintain gene expression modules controlling type I & II AEC identity and function. C) Determine how Arid1a/Arid1b-mediated chromatin remodeling contributes to the lung epithelial repair response following influenza infection. These studies will provide conceptual advances in our understanding of how mature alveolar epithelial cells are established and maintained, how the chromatin accessibility landscape interacts with previously well- defined transcription factor networks, and how chromatin remodeling directs the normal repair process after lung injury. Emerging epigenomic tools and systems biology approaches will be applied to the epithelium for the first time. Taken together, these data will inform future translational studies seeking to understand how alterations in the epigenome contribute to lung disease, and will provide a foundation for future efforts to manipulate the lung’s epigenomic code to restore normal lung structure and function.

项目摘要： 人们越来越认识到染色质状态的变化与广泛的范围有关 肺部疾病，从支气管肺发育不良（BPD）到慢性阻塞性肺疾病 （COPD）。但是，这些变化的机制有助于这些疾病的发病机理， 以及如何操纵表观基因组以获得热益处，这在很大程度上是未知的。调节染色质 可访问性是一种重要的表观遗传机制，即使在重复遍历中，也可以控制基因表达 细胞分裂。但是，作为理解染色质可及性如何有助于的先决条件 疾病，染色质可及性模式首先建立和维持细胞身份的机制 必须定义肺部内。 该建议基于我们小组的研究，该研究鉴定了SWI/SNF蛋白ARID1A和ARID1B 作为在Sox9+肺部开发过程中发生的染色质可及性的关键介体变化 上皮干/祖细胞群。我们的数据表明，ARID1A或ARID1B的损失导致了 Sox9+祖细胞群体，肺泡分化受损以及呼吸引起的新生儿死亡 困扰。另外，ARID1A直接与NKX2-1和SOX9相互作用。现在的中心假设 建议是ARID1A和ARID1B与关键的肺发育TF相互作用，将SWI/SNF复合体引导到 在特定局部的重塑染色质，沉默祖细胞基因表达程序并促进 成熟牙槽上皮的成熟和功能。拟议的研究将：a）定义 ARID1A/ARID1B和较大的SWI/SNF复合物在建立成熟的肺泡细胞类型鉴定方面发挥作用 老鼠和人类。 b）确定SWI/SNF复合物重塑染色质的机制 与关键肺转录因子的联系，建立和维持控制基因表达模块 I型和II型AEC身份和功能。 c）确定ARID1A/ARID1B介导的染色质重塑如何贡献 影响肺部感染后的肺上皮修复反应。 这些研究将在我们对成熟肺泡上皮的理解中提供概念进步 建立和维护细胞，染色质可及性景观如何与以前的良好相互作用 定义的转录因子网络以及染色质重塑如何指导肺后正常修复过程 受伤。新兴的表观基因组工具和系统生物学方法将用于第一个上皮 时间。综上所述，这些数据将为未来的翻译研究提供信息，以了解如何改变 表观基因组有助于肺部疾病，并将为操纵肺的未来努力奠定基础 恢复正常肺结构和功能的表观基因组代码。