The CHARGE syndrome ortholog CHD-7 regulates TGF-β pathways in Caenorhabditis elegans

CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. Despite the public health relevance of this disorder, relevant cellular pathways a...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2022-04, Vol.119 (15), p.e2109508119-e2109508119
Main Authors: Jofré, Diego M, Hoffman, Dane K, Cervino, Ailen S, Hahn, Gabriella M, Grundy, McKenzie, Yun, Sijung, Amrit, Francis R G, Stolz, Donna B, Godoy, Luciana F, Salvatore, Esteban, Rossi, Fabiana A, Ghazi, Arjumand, Cirio, M Cecilia, Yanowitz, Judith L, Hochbaum, Daniel
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Body size
Caenorhabditis elegans - metabolism
Caenorhabditis elegans Proteins - metabolism
CHARGE Syndrome
Collagen
Craniofacial growth
Developmental disabilities
DNA helicase
DNA Helicases - genetics
DNA Helicases - metabolism
DNA-binding protein
Embryos
Epistasis
Extracellular matrix
Gene expression
Growth factors
Heart
Larva
Lethality
Life span
Morphogenesis
Mutation
Nematodes
Nervous system
Public health
Signal Transduction
Signaling
Size determination
Transcriptomics
Transforming Growth Factor beta - genetics
Transforming Growth Factor beta - metabolism
Transforming growth factor-b
Tumors
Vertebrates
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Summary:CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. Despite the public health relevance of this disorder, relevant cellular pathways and targets of CHD7 that relate to disease pathology are still poorly understood. Here we report that chd-7, the nematode ortholog of Chd7, is required for dauer morphogenesis, lifespan determination, stress response, and body size determination. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the DAF-7/ tumor growth factor-β (TGF-β) pathway. Epistatic analysis places CHD-7 at the level of the DAF-3/DAF-5 complex, but we found that CHD-7 also directly impacts the expression of multiple components of this pathway. Transcriptomic analysis revealed that chd-7 mutants fail to repress daf-9 for execution of the dauer program. In addition, CHD-7 regulates the DBL-1/BMP pathway components and shares roles in male tail development and cuticle synthesis. To explore a potential conserved function for chd-7 in vertebrates, we used Xenopus laevis embryos, an established model to study craniofacial development. Morpholino-mediated knockdown of Chd7 led to a reduction in col2a1 messenger RNA (mRNA) levels, a collagen whose expression depends on TGF-β signaling. Both embryonic lethality and craniofacial defects in Chd7-depleted tadpoles were partially rescued by overexpression of col2a1 mRNA. We suggest that Chd7 has conserved roles in regulation of the TGF-β signaling pathway and pathogenic Chd7 could lead to a defective extracellular matrix deposition.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2109508119