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Dr. Liesa’s participated in a new study led by Dr. Wilson at the Center of Regenerative Medicine at Boston University, published in Science Advances titled “CRISPRi interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells”

    An iPSC-CRISPRi platform allowed to investigate the functional significance of nine genes associated with Chronic Obstructive Pulmonary Disease (COPD) by GWAS. This platform allowed to determine that desmoplakin (DSP) modulates the ability of iPSC -derived alveolar type 2 cells to respond to injury. Mechanistically, desmoplakin modulated mitochondrial fuel preference and proliferation.

    Abstract

    Genome-wide association studies (GWAS) have identified dozens of loci associated with chronic obstructive pulmonary disease (COPD) susceptibility; however, the function of associated genes in the cell type(s) affected in disease remains poorly understood, partly due to a lack of cell models that recapitulate human alveolar biology. Here, we apply CRISPR interference to interrogate the function of nine genes implicated in COPD by GWAS in induced pluripotent stem cell–derived type 2 alveolar epithelial cells (iAT2s). We find that multiple genes implicated by GWAS affect iAT2 function, including differentiation potential, maturation, and/or proliferation. Detailed characterization of the GWAS gene DSP demonstrates that it regulates iAT2 cell-cell junctions, proliferation, mitochondrial function, and response to cigarette smoke–induced injury. Our approach thus elucidates the biological function, as well as disease-relevant consequences of dysfunction, of genes implicated in COPD by GWAS in type 2 alveolar epithelial cells.

    Reference:

    Rhiannon B. Werder, Tao Liu, Kristine M. Abo, Jonathan Lindstrom-Vautrin, Carlos Villacorta-Martin, Jessie Huang, Anne Hinds, Nathan Boyer, Esther Bullitt, Marc Liesa, Edwin K. Silverman, Darrell N. Kotton, Michael H. Cho, Xiaobo Zhou, Andrew A. Wilson. CRISPR interference interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells. Science Advances 8(28), 2022. doi: 10.1126/sciadv.abo6566

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    Cover of the issue where the article was published
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