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.
Public Health Relevance Statement: In this post-genomic era rapid advancements in identifying new genes and genetic pathways provide exciting opportunities to evaluate genes and their gene products as new targets for therapeutic intervention. Recent efforts to understand the role of non-genic DNA elements in the human genome that may contribute to human disease are a continuing challenge. Through this proposal, we will investigate how the cystic fibrosis transmembrane conductance regulator (CFTR) gene is assembled in the context of the native human genome and the implications of how remodeling and folding of the CFTR gene in the human genome is guided by proteins regulating this process. Learning of the principles for the folding of the human genome may influence regulation of the CFTR gene and in turn predict outcomes for cystic fibrosis (CF) as a human disease.
