A genome-wide analysis of open chromatin in human tracheal epithelial cells reveals novel candidate regulatory elements for lung function
- Jared M Bischof1,2,
- Christopher J Ott1,2,
- Shih-Hsing Leir1,2,
- Nehal Gosalia1,2,
- Lingyun Song3,
- Darin London3,
- Terrence S Furey4,5,
- Calvin U Cotton6,7,
- Gregory E Crawford3,
- Ann Harris1,2
- 1Human Molecular Genetics Program, Children's Memorial Research Center, Chicago, Illinois, USA
- 2Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- 3Institute for Genome Science and Policy, Duke University, Durham, North Carolina, USA
- 4Department of Genetics, Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- 5Department of Biology, Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- 6Department of Pediatrics, Case Western University, School of Medicine, Cleveland, Ohio, USA
- 7Department of Physiology and Biophysics, Case Western University, School of Medicine, Cleveland, Ohio, USA
- Correspondence to Professor Ann Harris, Human Molecular Genetics Program, Children's Memorial Research Center, 2300 Children's Plaza, Box 211, Chicago, IL, 60614 USA;
Contributors JMB and AH designed experiments and analysed data. JB, CJO, S-HL, NG, LS and DL performed experiments. TSF, CUC and GEC contributed reagents/analytical tools. JMB and AH wrote the paper.
- Received 29 July 2011
- Accepted 18 November 2011
- Published Online First 14 December 2011
Background Distal cell-type-specific regulatory elements may be located at very large distances from the genes that they control and are often hidden within intergenic regions or in introns of other genes. The development of methods that enable mapping of regions of open chromatin genome wide has greatly advanced the identification and characterisation of these elements.
Methods Here we use DNase I hypersensitivity mapping followed by deep sequencing (DNase-seq) to generate a map of open chromatin in primary human tracheal epithelial (HTE) cells and use bioinformatic approaches to characterise the distribution of these sites within the genome and with respect to gene promoters, intronic and intergenic regions.
Results Genes with HTE-selective open chromatin at their promoters were associated with multiple pathways of epithelial function and differentiation. The data predict novel cell-type-specific regulatory elements for genes involved in HTE cell function, such as structural proteins and ion channels, and the transcription factors that may interact with them to control gene expression. Moreover, the map of open chromatin can identify the location of potentially critical regulatory elements in genome-wide association studies (GWAS) in which the strongest association is with single nucleotide polymorphisms in non-coding regions of the genome. We demonstrate its relevance to a recent GWAS that identifies modifiers of cystic fibrosis lung disease severity.
Conclusion Since HTE cells have many functional similarities with bronchial epithelial cells and other differentiated cells in the respiratory epithelium, these data are of direct relevance to elucidating the molecular basis of normal lung function and lung disease.
- Human tracheal epithelium
- open chromatin
- cis-acting regulatory elements
- lung cancer
- non-small cell lung cancer
- airway epithelium
- cystic fibrosis
- paediatric lung disease
Funding This work was supported by the National Institutes of Health, R01HL094585 (PI:AH), NHGRI U54 HG004363 (PI: GEC) and R01HD068901 (PI:AH).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.