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  1. Article ; Online: Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma

    Kyung Duk Koh / Luke R. Bonser / Walter L. Eckalbar / Ofer Yizhar-Barnea / Jiangshan Shen / Xiaoning Zeng / Kirsten L. Hargett / Dingyuan I. Sun / Lorna T. Zlock / Walter E. Finkbeiner / Nadav Ahituv / David J. Erle

    Cell Genomics, Vol 3, Iss 1, Pp 100229- (2023)

    2023  

    Abstract: Summary: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to ... ...

    Abstract Summary: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a CRISPR interference (CRISPRi)-based therapeutic approach to downregulate airway obstruction-inducing genes in a cell type- and IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) and acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) in primary human bronchial epithelial cells, we identified IL-13-responsive genes and regulatory elements. These sequences were functionally validated and optimized via massively parallel reporter assays (MPRAs) for IL-13-inducible activity. The top secretory cell-selective sequence from the MPRA, a novel, distal enhancer of the sterile alpha motif pointed domain containing E-26 transformation-specific transcription factor (SPDEF) gene, was utilized to drive CRISPRi and knock down SPDEF or mucin 5AC (MUC5AC), both involved in pathologic mucus production in asthma. Our work provides a catalog of cell type-specific genes and regulatory elements involved in IL-13 bronchial epithelial response and showcases their use for therapeutic purposes.
    Keywords enhancer ; IL-13 ; cell-specific ; CRISPRi ; HBEC ; SPDEF ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
    Subject code 572
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Ribonucleotide incorporation in yeast genomic DNA shows preference for cytosine and guanosine preceded by deoxyadenosine

    Sathya Balachander / Alli L. Gombolay / Taehwan Yang / Penghao Xu / Gary Newnam / Havva Keskin / Waleed M. M. El-Sayed / Anton V. Bryksin / Sijia Tao / Nicole E. Bowen / Raymond F. Schinazi / Baek Kim / Kyung Duk Koh / Fredrik O. Vannberg / Francesca Storici

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: Ribonucleoside monophosphates are incorporated by DNA polymerases into double-stranded DNA. Here, the authors use ribose-seq and Ribose-Map techniques to reveal that signatures and patterns of ribonucleotide incorporation in yeast mitochondrial and ... ...

    Abstract Ribonucleoside monophosphates are incorporated by DNA polymerases into double-stranded DNA. Here, the authors use ribose-seq and Ribose-Map techniques to reveal that signatures and patterns of ribonucleotide incorporation in yeast mitochondrial and nuclear DNA show preference for cytosine and guanosine preceded by deoxyadenosine.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Ribonucleotide incorporation in yeast genomic DNA shows preference for cytosine and guanosine preceded by deoxyadenosine

    Sathya Balachander / Alli L. Gombolay / Taehwan Yang / Penghao Xu / Gary Newnam / Havva Keskin / Waleed M. M. El-Sayed / Anton V. Bryksin / Sijia Tao / Nicole E. Bowen / Raymond F. Schinazi / Baek Kim / Kyung Duk Koh / Fredrik O. Vannberg / Francesca Storici

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: Ribonucleoside monophosphates are incorporated by DNA polymerases into double-stranded DNA. Here, the authors use ribose-seq and Ribose-Map techniques to reveal that signatures and patterns of ribonucleotide incorporation in yeast mitochondrial and ... ...

    Abstract Ribonucleoside monophosphates are incorporated by DNA polymerases into double-stranded DNA. Here, the authors use ribose-seq and Ribose-Map techniques to reveal that signatures and patterns of ribonucleotide incorporation in yeast mitochondrial and nuclear DNA show preference for cytosine and guanosine preceded by deoxyadenosine.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Epithelial miR-141 regulates IL-13–induced airway mucus production

    Sana Siddiqui / Kristina Johansson / Alex Joo / Luke R. Bonser / Kyung Duk Koh / Olivier Le Tonqueze / Samaneh Bolourchi / Rodriel A. Bautista / Lorna Zlock / Theodore L. Roth / Alexander Marson / Nirav R. Bhakta / K. Mark Ansel / Walter E. Finkbeiner / David J. Erle / Prescott G. Woodruff

    JCI Insight, Vol 6, Iss

    2021  Volume 5

    Abstract: IL-13–induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that ... ...

    Abstract IL-13–induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that airway epithelial miRNAs play roles in IL-13–induced mucus regulation. miR-141 is highly expressed in human and mouse airway epithelium, is altered in bronchial brushings from asthmatic subjects at baseline, and is induced shortly after airway allergen exposure. We established a CRISPR/Cas9-based protocol to target miR-141 in primary human bronchial epithelial cells that were differentiated at air-liquid-interface, and goblet cell hyperplasia was induced by IL-13 stimulation. miR-141 disruption resulted in decreased goblet cell frequency, intracellular MUC5AC, and total secreted mucus. These effects correlated with a reduction in a goblet cell gene expression signature and enrichment of a basal cell gene expression signature defined by single cell RNA sequencing. Furthermore, intranasal administration of a sequence-specific mmu-miR-141-3p inhibitor in mice decreased Aspergillus-induced secreted mucus and mucus-producing cells in the lung and reduced airway hyperresponsiveness without affecting cellular inflammation. In conclusion, we have identified a miRNA that regulates pathological airway mucus production and is amenable to therapeutic manipulation through an inhaled route.
    Keywords Pulmonology ; Medicine ; R
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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