Genes and compounds that increase type VII collagen expression as potential treatments for dystrophic epidermolysis bullosa
Dystrophic epidermolysis bullosa (DEB) is a skin‐blistering disease caused by mutations in COL7A1, which encodes type VII collagen (C7). There is no cure for DEB, but previous work has shown potential therapeutic benefit of increased production of even partially functional C7. Genome‐wide screens us...
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Published in | Experimental dermatology Vol. 31; no. 7; pp. 1065 - 1075 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Denmark
Wiley Subscription Services, Inc
01.07.2022
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Subjects | |
Online Access | Get full text |
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Summary: | Dystrophic epidermolysis bullosa (DEB) is a skin‐blistering disease caused by mutations in COL7A1, which encodes type VII collagen (C7). There is no cure for DEB, but previous work has shown potential therapeutic benefit of increased production of even partially functional C7. Genome‐wide screens using CRISPR‐Cas9 have enabled the identification of genes involved in cancer development, drug resistance and other genetic diseases, suggesting that they could be used to identify drivers of C7 production. A keratinocyte C7 reporter cell line was created and used in a genome‐wide CRISPR activation (CRISPRa) screen to identify genes and pathways that increase C7 expression. The CRISPRa screen results were used to develop a targeted drug screen to identify compounds that upregulate C7 expression. The C7_tdTomato cell line was validated as an effective reporter for detection of C7 upregulation. The CRISPRa screen identified DENND4B and TYROBP as top gene hits plus pathways related to calcium uptake and immune signalling in C7 regulation. The targeted drug screen identified several compounds that increase C7 expression in keratinocytes, of which kaempferol, a plant flavonoid, also significantly increased C7 mRNA and protein in DEB patient cells. |
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Bibliography: | Elizabeth L. Thompson and Michael Pickett‐Leonard should be considered joint first authors. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author Contributions ELT and MPL should be considered joint first authors. Conceptualization: ELT, MPL; Data Curation: ELT, MPL; Formal Analysis: ELT, MPL; Funding Acquisition: ELT, FA, JT; Investigation: ELT, MPL, MJR, WC; Methodology: ELT, MPL; Project Administration: ELT, MPL; Resources: ELT, JT; Software: MPL; Supervision: FA, JT; Validation: ELT, MPL; Visualization: ELT, MPL; Writing – Original Draft: ELT, MPL; Writing – Review and Editing: ELT, MPL, MJR, WC, FA, JT. |
ISSN: | 0906-6705 1600-0625 |
DOI: | 10.1111/exd.14555 |