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: 10616535
• 负责人: Debora Sinner
• 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/10616535
• 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 Modeling; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Code; Cre driver; DNA Sequence; Data; Data Set; Development; Disease; Disease Progression; Distal; Doxycycline; Drosophila snf protein; Epigenetic Process; Epithelial Cells; Epithelium; Family member; Flow Cytometry; Foundations; Future; Gene Combinations; Gene Expression; Genetic Transcription; Histology; Homeostasis; Human; Impairment; Information Systems; Injury; LoxP-flanked allele; Lung; Lung diseases; Mediating; Mediator; 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; 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 cell population; stem cell proliferation; 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.

项目概要： 越来越多的人认识到，染色质状态的变化与广泛的免疫反应有关。 肺部疾病，从支气管肺发育不良（BPD）到慢性阻塞性肺病 （COPD）。然而，这些变化导致这些疾病发病的机制， 以及如何操纵表观基因组以获得治疗益处，在很大程度上仍是未知的。染色质的调节 可接近性是一种重要的表观遗传机制，通过它控制基因表达，即使在重复的 细胞分裂然而，作为了解改变的染色质可及性如何有助于 疾病，染色质可及性模式首先建立和维持细胞身份的机制 肺内必须明确。 该建议基于我们小组的研究，该研究鉴定了SWI/SNF蛋白Arid 1a和Arid 1b 作为SOX 9+肺发育过程中发生的染色质可及性变化的关键介质 上皮干/祖细胞群。我们的数据表明，Arid 1a或Arid 1b的缺失导致了 SOX 9+祖细胞群、受损的肺泡分化和由于呼吸道感染引起的新生儿死亡 痛苦此外，ARID 1A直接与NKX 2 -1和SOX 9相互作用。目前的核心假设是 建议ARID 1A和ARID 1B与关键的肺发育TF相互作用，以指导SWI/SNF复合物 在特定的基因座重塑染色质，沉默祖细胞基因表达程序，并促进 成熟肺泡上皮的成熟和功能。拟议的研究将：A）界定 Arid 1a/Arid 1b和更大的SWI/SNF复合物在建立成熟的肺泡细胞类型鉴定中起作用。 老鼠和人类。B）鉴定SWI/SNF复合物重塑染色质的机制， 与肺关键转录因子结合，建立和维持基因表达模块， I型和II型AEC的特性和功能。C）确定Arid 1a/Arid 1b介导的染色质重塑如何贡献 与流感感染后肺上皮修复反应有关。 这些研究将为我们理解成熟的肺泡上皮细胞是如何 细胞的建立和维持，染色质可及性景观如何与以前良好的相互作用， 定义的转录因子网络，以及染色质重塑如何指导肺损伤后的正常修复过程。 损伤新兴的表观基因组工具和系统生物学方法将首次应用于上皮细胞 时间总之，这些数据将为未来的翻译研究提供信息，以了解基因组中的改变是如何发生的。 表观基因组有助于肺部疾病，并将为未来操纵肺部疾病的努力提供基础。 表观基因组密码恢复正常的肺结构和功能。

项目成果

Beyond diagnostic yield: prenatal exome sequencing results in maternal, neonatal, and familial clinical management changes.

• DOI: 10.1038/s41436-020-01067-9
• 发表时间: 2021-05
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Tolusso LK;Hazelton P;Wong B;Swarr DT
• 通讯作者: Swarr DT

PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors.

• DOI: 10.7554/elife.67954
• 发表时间: 2022-08-17
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Khattar, Divya;Fernandes, Sharlene;Snowball, John;Guo, Minzhe;Gillen, Matthew C.;Jain, Suchi Singh;Sinner, Debora;Zacharias, William;Swarr, Daniel T.;Morrisey, Edward E.
• 通讯作者: Morrisey, Edward E.