CHD6 regulates the topological arrangement of the CFTR locus

Ana Sancho, Si De Li, Thankam Paul, Fan Zhang, Francesca Aguilo, Ajay Vashisht, Natarajan Balasubramaniyan, Neal S. Leleiko, Frederick J. Suchy, James A. Wohlschlegel, Weijia Zhang, Martin J. Walsh

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The control of transcription is regulated through thewell-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 intrachromosomal 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 CHD6are consistent with the role described previously for CTCF in CFTR regulation. Our results nowreveal 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.

Original languageEnglish
Pages (from-to)2724-2732
Number of pages9
JournalHuman Molecular Genetics
Volume24
Issue number10
DOIs
StatePublished - 15 May 2015

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