Underlying chromatin architecture defines functionality for CFTR expression

底层染色质架构定义了 CFTR 表达的功能

基本信息

批准号：
9789271
负责人：
Martin John Walsh
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789271
关键词：
ATAC-seq Address Affinity Affinity Chromatography Alleles Architecture Binding Proteins Biochemistry Biological Biological Sciences Biology CCCTC-binding factor CHD4 gene CRISPR/Cas technology Cells ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Code Complement Complex Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator DNA Deacetylase Dependence Development Disease Outcome Elements Engineering Enhancers Environment Epigenetic Process Epithelial Cells Fibroblasts Funding Gene Expression Genes Genetic Genetic Polymorphism Genetic Transcription Genome engineering Genomic Segment Genomics Goals Guide RNA Histone Deacetylase Inhibitor Histones Human Human Genome Intestines Introns Knowledge Learning Link Lung Maps Mass Spectrum Analysis Measures Mediating Methods Molecular Mutation Nucleosomes Pancreatic duct Pancreatitis Pathway interactions Phenotype Positioning Attribute Post-Translational Protein Processing Predisposition Prenatal Diagnosis Procedures Process Protein Binding Domain Proteins Proteome Proteomics RNA Regulation Regulator Genes Repression Research Project Grants Resolution Role Shapes Site Spectrophotometry Technology Therapeutic Therapeutic Intervention Transcript United States National Institutes of Health base cell type chromatin remodeling epigenome expectation experience functional genomics gene product gene repression genome editing helicase histone modification human disease insight knock-down mouse model new therapeutic target novel novel strategies outcome prediction penis foreskin public health relevance targeted treatment transcription termination transcriptome sequencing

项目摘要

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.

项目概要：本申请的总体目标是阐明染色质重塑对囊性纤维化跨膜电导调节基因（CFTR）基因座的调节。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会带来新的方法靶向治疗以丰富与特定的CFTR表达一致的弱（或差）CFTR表达 CFTR 突变。这些新知识与理解复杂的总体期望相吻合 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，其中产前诊断和治疗取得重大进展。虽然许多编码突变 CFTR 基因已被鉴定并与 CF 作为一种人类疾病、各种非基因多态性仍然是与 CFTR 基因相关的疾病结果谱的一个未知因素它的表达。我们和其他人提供了有关 CFTR 背后的染色质架构的新见解产生选择性上皮细胞类型和 CFTR 转录发育控制的位点。在在之前的资助周期中，我们已经确定并确认了染色解旋酶 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 在培养物染色质环境中如何排列的因素的新见解和原代细胞。通过所提出的目标，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环境下进行引导。我们预计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方式的理解适应 CFTR 表达。