Underlying chromatin architecture defines functionality for CFTR expression

项目概要： 本申请的总体目标是阐明染色质重塑对细胞凋亡的生物学影响。 囊性纤维化跨膜传导调节基因（CFTR）位点的调节。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有助于新的方法 涉及用于富集弱（或差）CFTR表达的靶向疗法，所述弱（或差）CFTR表达似乎与特异性表达一致。 CFTR突变。这一新的知识与理解复杂的整体期望相吻合 CFTR表达与囊性纤维化（CF）的关系。CF仍然是一个突出的遗传缺陷， 在产前诊断和治疗方面取得了重大进展。虽然许多编码突变在 CFTR基因已被鉴定，并与CF作为一种人类疾病偶然相关，各种非基因 多态性仍然是一个未知的贡献者，疾病结果的谱与CFTR基因有关， 它的表达。我们和其他人提供了关于CFTR背后的染色质结构的新见解 该基因座引起选择性上皮细胞类型和CFTR转录的发育控制。在 在上一个资助周期中，我们已经确定并证实了染色体解旋酶DNA结合结构域的作用 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 提供了新的见解的因素，支配CFTR是如何安排在染色质的背景下，培养 原代细胞通过提出的目标，我们期望共同提供基本框架， 确定CFTR表达如何在天然染色质背景下引导。我们设想这些研究 将加深我们对染色质调节因子用于塑造上皮细胞表观基因组的手段的理解， 容纳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.