title: CHD6 regulates the topological arrangement of the CFTR locus.
abstract: The control of transcription is regulated through the well-coordinated spatial and temporal interactions between distal genomic regulatory elements required for specialized cell-type and developmental gene expression programs. With recent findings CFTR has served as a model to understand the principles that govern genome-wide and topological organization of distal intra-chromosomal contacts as it relates to transcriptional control. This is due to the extensive characterization of the DNase hypersensitivity sites, modification of chromatin, transcription factor binding sites and the arrangement of these sites in CFTR consistent with the restrictive expression in epithelial cell types. Here, we identified CHD6 from a screen among several chromatin-remodeling proteins as a putative epigenetic modulator of CFTR expression. Moreover, our findings of CTCF interactions with CHD6 are consistent with the role described previously for CTCF in CFTR regulation. Our results now reveal that the CHD6 protein lies within the infrastructure of multiple transcriptional complexes, such as the FACT, PBAF, PAF1C, Mediator, SMC/Cohesion and MLL complexes. This model underlies the fundamental role CHD6 facilitates by tethering cis-acting regulatory elements of CFTR in proximity to these multi-subunit transcriptional protein complexes. Finally, we indicate that CHD6 structurally coordinates a three-dimensional stricture between intragenic elements of CFTR bound by several cell-type specific transcription factors, such as CDX2, SOX18, HNF4α and HNF1α. Therefore, our results reveal new insights into the epigenetic regulation of CFTR expression, whereas the manipulation of CFTR gene topology could be considered for treating specific indications of cystic fibrosis and/or pancreatitis.
authors: Departments of Pediatrics, Structural and Chemical Biology.
authors: Ana
authors: A
authors: Sancho
authors: Departments of Pediatrics.
authors: SiDe
authors: S
authors: Li
authors: Department of Paediatrics, St. George's Hospital, University of London, London SW17 0QT, UK.
authors: Thankam
authors: T
authors: Paul
authors: Laboratory of Bioinformatics, Division of Nephrology, Department of Medicine.
authors: Fan
authors: F
authors: Zhang
authors: Departments of Pediatrics, Structural and Chemical Biology.
authors: Francesca
authors: F
authors: Aguilo
authors: Department of Biological Chemistry and the Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Ajay
authors: A
authors: Vashisht
authors: Children's Hospital Research Institute of Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA and.
authors: Natarajan
authors: N
authors: Balasubramaniyan
authors: Department of Pediatrics, Division of Gastroenterology, Hasbro Children's Hospital, Brown University School of Medicine, Providence, NY, USA.
authors: Neal S
authors: NS
authors: Leleiko
authors: Children's Hospital Research Institute of Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA and.
authors: Frederick J
authors: FJ
authors: Suchy
authors: Department of Biological Chemistry and the Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: James A
authors: JA
authors: Wohlschlegel
authors: Laboratory of Bioinformatics, Division of Nephrology, Department of Medicine.
authors: Weijia
authors: W
authors: Zhang
authors: Departments of Pediatrics, Structural and Chemical Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, martin.walsh@mssm.edu.
authors: Martin J
authors: MJ
authors: Walsh
mesh_terms: D002843:Chromatin / Q000737:chemistry*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004265:DNA Helicases / Q000378:metabolism*; D044127:Epigenesis, Genetic; D056426:Genetic Loci; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D050436:Regulatory Elements, Transcriptional; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; C583979:CHD6 protein, human; D002843:Chromatin; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004265:DNA Helicases
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