Molecular characterization of gene regulatory networks in primary human tracheal and bronchial epithelial cells

Gillen, Austin E.; Yang, Rui; Cotton, Calvin U.; Perez, Aura; Randell, Scott H.; Leir, Shih Hsing; Harris, Ann

doi:10.1016/j.jcf.2018.01.009

Cited by 10 publications

(11 citation statements)

References 32 publications

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“…ELF5 is absent from commonly used human airway epithelial cell lines, though it is expressed at low levels in primary HBE and HTE cells . Hence, in order to pursue our interest in ELF5 and the 5’ end of the chr11p13 region we used other epithelial cell lines (T47D and LNCaP) that express both ELF5 and EHF .…”

Section: Discussionmentioning

confidence: 99%

“…ELF5 is absent from commonly used human airway epithelial cell lines, though it is expressed at low levels in primary HBE and HTE cells. 42 Hence, in order to pursue our interest in ELF5 and the 5' end of the chr11p13 region we used other epithelial cell lines (T47D and LNCaP) that express both ELF5 and EHF. Analysis of these lines re- Two sites are of particular interest: 11.2513, is a peak of open chromatin in primary HTE cells 45 but lacks H3K27ac in the airway cell types 25 so was not investigated further; also of interest is a novel element immediately 3' to the EHF locus, which is not evident in primary HTE cells, but is clearly seen in both ELF5-expressing cell types studied here.…”

Section: Discussionmentioning

confidence: 99%

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Coordinate regulation of ELF5 and EHF at the chr11p13 CF modifier region

Swahn

Ebron

Lamar

et al. 2019

J Cellular Molecular Medi

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E74‐like factor 5 (ELF5) and ETS‐homologous factor (EHF) are epithelial selective ETS family transcription factors (TFs) encoded by genes at chr11p13, a region associated with cystic fibrosis (CF) lung disease severity. EHF controls many key processes in lung epithelial function so its regulatory mechanisms are important. Using CRISPR/Cas9 technology, we removed three key cis‐regulatory elements (CREs) from the chr11p13 region and also activated multiple open chromatin sites with CRISPRa in airway epithelial cells. Deletion of the CREs caused subtle changes in chromatin architecture and site‐specific increases in EHF and ELF5. CRISPRa had most effect on ELF5 transcription. ELF5 levels are low in airway cells but higher in LNCaP (prostate) and T47D (breast) cancer cells. ATAC‐seq in these lines revealed novel peaks of open chromatin at the 5’ end of chr11p13 associated with an expressed ELF5 gene. Furthermore, 4C‐seq assays identified direct interactions between the active ELF5 promoter and sites within the EHF locus, suggesting coordinate regulation between these TFs. ChIP‐seq for ELF5 in T47D cells revealed ELF5 occupancy within EHF introns 1 and 6, and siRNA‐mediated depletion of ELF5 enhanced EHF expression. These results define a new role for ELF5 in lung epithelial biology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Coordinate regulation of ELF5 and EHF at the chr11p13 CF modifier region

Swahn

Ebron

Lamar

et al. 2019

J Cellular Molecular Medi

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“…Variation in infection and replication levels of viruses between donors was regularly observed (57)(58)(59)(60). Explanations could be differences in: receptor presence or distribution, cytokine responses, donors and environmental factors (61,62). It is dependent on the research question how important these dissimilarities are.…”

Section: Considerations For Use Of Primary Cellsmentioning

confidence: 99%

In Vitro Modelling of Respiratory Virus Infections in Human Airway Epithelial Cells – A Systematic Review

et al. 2021

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Respiratory tract infections (RTI) are a major cause of morbidity and mortality in humans. A large number of RTIs is caused by viruses, often resulting in more severe disease in infants, elderly and the immunocompromised. Upon viral infection, most individuals experience common cold-like symptoms associated with an upper RTI. However, in some cases a severe and sometimes life-threatening lower RTI may develop. Reproducible and scalable in vitro culture models that accurately reflect the human respiratory tract are needed to study interactions between respiratory viruses and the host, and to test novel therapeutic interventions. Multiple in vitro respiratory cell culture systems have been described, but the majority of these are based on immortalized cell lines. Although useful for studying certain aspects of viral infections, such monomorphic, unicellular systems fall short in creating an understanding of the processes that occur at an integrated tissue level. Novel in vitro models involving primary human airway epithelial cells and, more recently, human airway organoids, are now in use. In this review, we describe the evolution of in vitro cell culture systems and their characteristics in the context of viral RTIs, starting from advances after immortalized cell cultures to more recently developed organoid systems. Furthermore, we describe how these models are used in studying virus-host interactions, e.g. tropism and receptor studies as well as interactions with the innate immune system. Finally, we provide an outlook for future developments in this field, including co-factors that mimic the microenvironment in the respiratory tract.

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“…We downloaded human bronchial epithelial (HBE) RNA-seq data from Gillen et al via the European Nucleotide Archive to use as a benign lung tissue model [27]. This data set contains gene expression data for primary HBE cells cultured from three different donors and also normal human bronchial epithelial (NHBE) cells (a mixture of HBE and human tracheal epithelial cells purchased from Lonza Bioscience (CC-2541)).…”

Section: Differential Expression Of Benign and Malignant Cancer Cell Linesmentioning

confidence: 99%

A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy

et al. 2021

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Background Advances in cancer biology are increasingly dependent on integration of heterogeneous datasets. Large-scale efforts have systematically mapped many aspects of cancer cell biology; however, it remains challenging for individual scientists to effectively integrate and understand this data. Results We have developed a new data retrieval and indexing framework that allows us to integrate publicly available data from different sources and to combine publicly available data with new or bespoke datasets. Our approach, which we have named the cancer data integrator (CanDI), is straightforward to implement, is well documented, and is continuously updated which should enable individual users to take full advantage of efforts to map cancer cell biology. We show that CanDI empowered testable hypotheses of new synthetic lethal gene pairs, genes associated with sex disparity, and immunotherapy targets in cancer. Conclusions CanDI provides a flexible approach for large-scale data integration in cancer research enabling rapid generation of hypotheses. The CanDI data integrator is available at https://github.com/GilbertLabUCSF/CanDI.

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Molecular characterization of gene regulatory networks in primary human tracheal and bronchial epithelial cells

Abstract: These data are a valuable resource for functional genomics analysis of airway epithelial tissues in human disease.

Cited by 10 publications

References 32 publications

Coordinate regulation of ELF5 and EHF at the chr11p13 CF modifier region

Coordinate regulation of ELF5 and EHF at the chr11p13 CF modifier region

In Vitro Modelling of Respiratory Virus Infections in Human Airway Epithelial Cells – A Systematic Review

A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy

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