Genes and compounds that increase type VII collagen expression as potential treatments for dystrophic epidermolysis bullosa.
CRISPR-cas systems
kaempferol
keratinocytes
precision medicine
rare diseases
Journal
Experimental dermatology
ISSN: 1600-0625
Titre abrégé: Exp Dermatol
Pays: Denmark
ID NLM: 9301549
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
07
02
2022
received:
28
09
2021
accepted:
27
02
2022
pubmed:
5
3
2022
medline:
16
7
2022
entrez:
4
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35243691
doi: 10.1111/exd.14555
pmc: PMC9318024
mid: NIHMS1822648
doi:
Substances chimiques
COL7A1 protein, human
0
Collagen Type VII
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1065-1075Subventions
Organisme : NIA NIH HHS
ID : T32 AG029796
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR063070
Pays : United States
Organisme : NHGRI NIH HHS
ID : R21 HG010380
Pays : United States
Informations de copyright
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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