| RRC ID |
81878
|
| Author |
Barnada SM, Giner de Gracia A, Morenilla-Palao C, López-Cascales MT, Scopa C, Waltrich FJ Jr, Mikkers HMM, Cicardi ME, Karlin J, Trotti D, Peterson KA, Brugmann SA, Santen GWE, McMahon SB, Herrera E, Trizzino M.
|
| Title |
ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial-to-mesenchymal transition in cranial neural crest specification.
|
| Journal |
Am J Hum Genet
|
| Abstract |
The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of individuals with CSS harbor variants in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS-patient-derived ARID1A+/- induced pluripotent stem cells to model CNCC specification, we discovered that ARID1A-haploinsufficiency impairs epithelial-to-mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at post-migratory neural crest stages elicits ectopic delamination from the neural tube. These findings reveal an essential ARID1A-ZIC2 axis essential for EMT and CNCC delamination.
|
| Volume |
111(10)
|
| Pages |
2232-2252
|
| Published |
2024-10-3
|
| DOI |
10.1016/j.ajhg.2024.07.022
|
| PII |
S0002-9297(24)00283-0
|
| PMID |
39226899
|
| PMC |
PMC11480806
|
| MeSH |
Abnormalities, Multiple
Animals
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Enhancer Elements, Genetic / genetics
Epithelial-Mesenchymal Transition* / genetics
Face* / abnormalities
Face* / embryology
Foot Deformities, Congenital / genetics
Foot Deformities, Congenital / pathology
Gene Expression Regulation, Developmental
Hand Deformities, Congenital* / genetics
Hand Deformities, Congenital* / pathology
Haploinsufficiency
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Intellectual Disability* / genetics
Mice
Micrognathism* / genetics
Neck* / abnormalities
Neck* / embryology
Neural Crest* / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Transcription Factors* / genetics
Transcription Factors* / metabolism
|
| IF |
10.502
|
| Resource |
| Mice |
RBRC00165 |
