Underlying chromatin architecture defines functionality for CFTR expression

项目总结： 这项应用的总体目标是阐明染色质重塑对 囊性纤维化跨膜传导调节基因(CFTR)基因的调控。反过来，一部小说 了解与基因转录相关的染色质重塑过程可能会使新的方法成为可能 靶向治疗以丰富弱(或差)CFTR表达，这些表达似乎与特定的 CFTR基因突变。这一新知识与理解复杂事物的总体期望不谋而合。 CFTR的表达与囊性纤维化的关系Cf仍然是一个突出的遗传缺陷，在 产前诊断和治疗取得重大进展。虽然许多编码突变存在于 CFTR基因已经被鉴定出来，并作为一种人类疾病与CF偶然连锁，各种非基因 多态仍然是一个未知的因素，疾病结果的谱与CFTR基因和 它的表情。我们和其他人对CFTR背后的染色质结构提供了新的见解 导致选择性上皮细胞类型和CFTR转录的发育控制的基因座。在 在之前的资金周期中，我们已经确定并确认了染色体解旋酶DNA结合域的作用 蛋白6(CHD6)位于天然染色质中拓扑结构良好的CFTR基因的核心。这有 提供了关于控制CFTR在培养的染色质环境中如何排列的因素的新见解 和原代细胞。总之，通过提出的目标，我们希望提供基本框架，以 确定CFTR在天然染色质环境下的表达是如何引导的。我们设想这些研究 将加深我们对染色质调节器用来塑造上皮细胞表观基因组的方法的理解 适应cftr表达。

PROJECT SUMMARY: The overall goal of this application is to elucidate the biological impact of chromatin remodeling for the regulation of the cystic fibrosis transmembrane conductance regulator gene (CFTR) locus. In turn, a novel understanding of chromatin remodeling processes linked with gene transcription may enable novel approaches to targeted therapy for enriching weak (or poor) CFTR expression that appear consistent with specific mutations in CFTR. This new knowledge coincides with the overall expectation to understand the complex relationship of CFTR expression to cystic fibrosis (CF). CF remains a prominent genetic defect where significant progress has been made in prenatal diagnosis and treatment. While many coding mutations in the CFTR gene have been identified and casually linked to CF as a human disease, various non-genic polymorphisms remain an unknown contributor the spectrum of disease outcomes link to the CFTR gene and its expression. We, and others, have provided new insight about the chromatin architecture behind the CFTR locus that gives rise to the selective epithelial cell-type and development control of CFTR transcription. In the previous funding cycle we have identified and confirmed the role of the chromo-helicase DNA binding domain protein 6 (CHD6) lies at the core of the topologically well-organized CFTR gene in native chromatin. This has provided new insight as to the factors that govern how CFTR is arranged in the chromatin context in cultured and primary cells. Together, through the aims proposed we expect to provide the fundamental framework to determine how CFTR expression is guiding under a native chromatin context. We envision that these studies will deepen our understanding of the means chromatin regulators use to shape the epithelial cell epigenome to accommodate CFTR expression.