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

项目总结： 人们越来越认识到，染色质状态的变化与广泛的 肺部疾病，从支气管肺发育不良(BPD)到慢性阻塞性肺疾病 (COPD)。然而，这些变化促进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，在很大程度上仍不清楚。染色质的调制 可及性是一种重要的表观遗传机制，通过它可以控制基因的表达，即使是在重复的情况下 细胞分裂。然而，作为理解染色质可及性改变如何有助于 疾病，染色质可及性模式首先建立和维持细胞特性的机制 必须定义肺内。 这一建议是基于我们小组的研究，该研究确定了SWI/SNF蛋白ARID1a和Arid1b 作为SOX9肺发育过程中染色质可及性变化的关键介质 上皮干/祖细胞群体。我们的数据表明，ARID1a或Arid1b的丢失导致了 SOX9祖细胞数量、肺泡分化障碍和新生儿呼吸性死亡 苦恼。此外，ARID1A还与NKX2-1和SOX9直接相互作用。当前的中心假设 建议ARID1A和ARID1B与关键的肺发育因子相互作用，引导SWI/SNF复合体 重塑特定位点的染色质，沉默祖细胞基因表达程序，促进 成熟的肺泡上皮的成熟和功能。拟议的研究将：a)界定 ARID1a/Arid1b和较大的SWI/SNF复合体在建立成熟的肺泡细胞类型中发挥作用 老鼠和人类。B)确定SWI/snf复合体重塑染色质的机制(S) 与关键的肺转录因子结合，建立和维护基因表达调控模块 I型和II型AEC的身份和功能。C)确定ARID1a/Arid1b介导的染色质重塑如何起作用 对流感感染后的肺上皮修复反应的影响。 这些研究将为我们理解肺泡上皮如何成熟提供概念上的进展。 细胞被建立和维护，染色质可及性景观如何与之前良好的- 明确的转录因子网络，以及染色质重塑如何指导肺损伤后的正常修复过程 受伤。新出现的表观基因组学工具和系统生物学方法将首次应用于上皮细胞 时间到了。综上所述，这些数据将为未来的翻译研究提供信息，试图了解这些变化是如何 表观基因组有助于肺部疾病，并将为未来操纵肺的 恢复正常肺结构和功能的表观基因组密码。

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.