Abstract
The contribution of chromatin dynamics to the regulation of human disease-associated loci such as the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been the focus of intensive experimentation for many years. Recent technological advances in the analysis of transcriptional mechanisms across the entire human genome have greatly facilitated these studies. In this review we describe the complex machinery of tissue-specific regulation of CFTR expression, and put earlier observations in context by incorporating them into datasets generated by the most recent genomics methods. Though the gene promoter is required for CFTR expression, cell-type specific regulatory elements are located elsewhere in the gene and in flanking intergenic regions. Probably within its own topological domain established by the architectural proteins CTCF and cohesin, the CFTR locus utilizes chromatin dynamics to remodel nucleosomes, recruit cell-selective transcription factors, and activate intronic enhancers. These cis-acting elements are then brought to the gene promoter by chromatin looping mechanisms, which establish long-range interactions across the locus. Despite its complexity, the CFTR locus provides a paradigm for elucidating the critical role of chromatin dynamics in the transcription of individual human genes.
Highlights
One of the most intensively studied genes associated with human disease is the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encompasses 189 kb at chromosome 7q31.2.It encodes a 1480 amino acid protein, which primarily functions as a cAMP-dependent chloride ion channel [1,2,3] belonging to the ATP-binding cassette (ABC) transporter superfamily
The data discussed in the previous sections of this review convincingly demonstrate that multiple cis-regulatory elements are active at the CFTR locus, many of them located at a great distance (>100 kb) from the gene promoter
The extensive studies carried out over many years, which are discussed in this review, have provided substantial insights into the temporal and tissue-specific regulation of CFTR expression, though our understanding remains incomplete
Summary
One of the most intensively studied genes associated with human disease is the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encompasses 189 kb at chromosome 7q31.2. CFTR is expressed from early in gestation [11] and shows temporal regulation in the lung, with the fetal lung having higher levels of transcript than adult tissue [12,13,14] This complex pattern of coordinated tissue-specific and temporal regulation led to intensive investigation of the mechanisms controlling CFTR gene expression. Initial studies showed that the promoter contained binding sites for the transcription factors Sp1 and AP-1 [17], a cAMP response element (CRE), a CCAAT box [24,25,26], and a NF-κB binding site [27,28] These analyses did not identify the mechanisms by which tissue-specific CFTR expression is achieved. The lack of cell-type specific control elements in the promoter (defined here as ~2kb 5' to the translational start site) and the large size of the gene, with multiple long introns, led to the hypothesis that critical cis-regulatory elements might exist within the gene body itself or in distal upstream or downstream regions
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