PUBLICATION
Genetic regulation of ARID3B confers cleft lip with/without cleft palate susceptibility through LLPS-mediated transcriptional program
- Authors
- Li, X., Li, D., Lou, S., Lin, J., Gao, Y., Vona, B., Mi, C., Wang, L., Ma, L., Du, M., Pan, Y.
- ID
- ZDB-PUB-251002-4
- Date
- 2025
- Source
- Cell Reports 44: 116377116377 (Journal)
- Registered Authors
- Keywords
- CP: Genomics, GWAS, cleft lip and cleft palate, genetics regulation, phase separation
- MeSH Terms
-
- Animals
- Cell Movement/genetics
- Cleft Lip*/genetics
- Cleft Palate*/genetics
- DNA-Binding Proteins*/genetics
- DNA-Binding Proteins*/metabolism
- Genetic Predisposition to Disease*
- Humans
- Polymorphism, Single Nucleotide/genetics
- Transcription Factors*/genetics
- Transcription Factors*/metabolism
- Transcription, Genetic*
- Zebrafish/genetics
- PubMed
- 41032419 Full text @ Cell Rep.
Citation
Li, X., Li, D., Lou, S., Lin, J., Gao, Y., Vona, B., Mi, C., Wang, L., Ma, L., Du, M., Pan, Y. (2025) Genetic regulation of ARID3B confers cleft lip with/without cleft palate susceptibility through LLPS-mediated transcriptional program. Cell Reports. 44:116377116377.
Abstract
Genome-wide association studies have identified numerous loci associated with nonsyndromic cleft lip with/without cleft palate (nsCL/P). However, the causal genes within these loci remain to be systematically investigated. Through a multiomics screening strategy, we identified 20 candidate genes, with ARID3B emerging as the most significant risk gene for nsCL/P. Focusing on the ARID3B locus, we found a casual variant at rs1821848 that diminished the binding affinity of NR2C2, resulting in the upregulation of ARID3B. Notably, we observed the formation of ARID3B granules through liquid-liquid phase separation (LLPS) both in vivo and in vitro. This ARID3B-mediated LLPS could essentially recruit coactivators SMAD2/3 and establish enhancer activity necessary for initiating the gene profile related to nsCL/P. Ultimately, disrupting the LLPS of arid3b effectively rescued migration, apoptosis, and phenotype deficits in zebrafish models. This study systematically revealed biological functions of both rs1821848 and ARID3B during nsCL/P development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping