PUBLICATION
Chemical screens in a zebrafish model of CHARGE syndrome identifies small molecules that ameliorates disease like phenotypes in embryo
- Authors
- Asad, Z., Sachidanandan, C.
- ID
- ZDB-PUB-190507-30
- Date
- 2019
- Source
- European Journal of Medical Genetics 63(2): 103661 (Journal)
- Registered Authors
- Sachidanandan, Chetana
- Keywords
- CHARGE syndrome, CHD7, CHIC-35, DAPT, Drug discovery, M344, Procainamide, Zebrafish
- MeSH Terms
-
- DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors
- LIM-Homeodomain Proteins/genetics
- LIM-Homeodomain Proteins/metabolism
- Histone Deacetylase Inhibitors/pharmacology
- Histone Deacetylase Inhibitors/therapeutic use
- Embryo, Nonmammalian/diagnostic imaging
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/physiopathology
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Gene Knockdown Techniques
- Animals
- Receptors, Notch/antagonists & inhibitors
- Vorinostat/pharmacology*
- Vorinostat/therapeutic use
- CHARGE Syndrome/drug therapy*
- CHARGE Syndrome/genetics
- CHARGE Syndrome/physiopathology*
- Disease Models, Animal
- Dipeptides/pharmacology*
- Dipeptides/therapeutic use
- Animals, Genetically Modified
- DNA Helicases/genetics*
- DNA Helicases/metabolism
- Cartilage/drug effects
- Cartilage/pathology
- Sirtuin 1/antagonists & inhibitors
- Nerve Fibers, Myelinated/drug effects
- Nerve Fibers, Myelinated/pathology
- DNA-Binding Proteins/genetics*
- DNA-Binding Proteins/metabolism
- Neurons/drug effects
- Neurons/pathology
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Zebrafish/embryology*
- Zebrafish/genetics
- Procainamide/pharmacology*
- Procainamide/therapeutic use
- PubMed
- 31051269 Full text @ Eur. J. Med. Genet.
Citation
Asad, Z., Sachidanandan, C. (2019) Chemical screens in a zebrafish model of CHARGE syndrome identifies small molecules that ameliorates disease like phenotypes in embryo. European Journal of Medical Genetics. 63(2):103661.
Abstract
CHARGE syndrome is an autosomal dominant congenital disorder caused primarily by mutations in the CHD7 gene. Using a small molecule screen in a zebrafish model of CHARGE syndrome, we identified 4 compounds that rescue embryos from disease-like phenotypes. Our screen yielded DAPT, a Notch signaling inhibitor that could ameliorate the craniofacial, cranial neuronal and myelination defects in chd7 morphant zebrafish embryos. We discovered that Procainamide, an inhibitor of DNA methyltransferase 1, was able to recover the pattern of expression of isl2a, a cranial neuronal marker while also reducing the effect on craniofacial cartilage and myelination. M344, an inhibitor of Histone deacetylases had a strong recovery effect on craniofacial cartilage defects and could also modestly revert the myelination defects in zebrafish embryos. CHIC-35, a SIRT1 inhibitor partially restored the expression of isl2a in cranial neurons while causing a partial reversion of myelination and craniofacial cartilage defects. Our results suggest that a modular approach to phenotypic rescue in multi-organ syndromes might be a more successful approach to treat these disorders. Our findings also open up the possibility of using these compounds for other disorders with shared phenotypes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping