Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene-environment interaction

Autor(es)

Alvizi, Lucas ; Nani, Diogo ; Brito, Luciano Abreu ; Kobayashi, Gerson Shigeru ; Passos-Bueno, Maria Rita ; Mayor, Roberto

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 14, n. 1, p. 14-pg., 2023-05-24.

Resumo

Gene-environment interactions are believed to play a role in multifactorial phenotypes, although poorly described mechanistically. Cleft lip/palate (CLP), the most common craniofacial malformation, has been associated with both genetic and environmental factors, with little gene-environment interaction experimentally demonstrated. Here, we study CLP families harbouring CDH1/E-Cadherin variants with incomplete penetrance and we explore the association of pro-inflammatory conditions to CLP. By studying neural crest (NC) from mouse, Xenopus and humans, we show that CLP can be explained by a 2-hit model, where NC migration is impaired by a combination of genetic (CDH1 loss-of-function) and environmental (pro-inflammatory activation) factors, leading to CLP. Finally, using in vivo targeted methylation assays, we demonstrate that CDH1 hypermethylation is the major target of the pro-inflammatory response, and a direct regulator of E-cadherin levels and NC migration. These results unveil a gene-environment interaction during craniofacial development and provide a 2-hit mechanism to explain cleft lip/palate aetiology. Cleft lip and palate is a common birth defect thought to involve both genetic and environmental components in its etiology. Here they identify a mechanism involving inflammation and E-cadherin mutations that reduces neural crest migration, leading to craniofacial defects. (AU)

• Processo FAPESP: 17/11430-7 - Interação de fatores genéticos e epigenéticos em resposta à inflamação na predisposição às fissuras lábio-palatinas
• Beneficiário: Lucas Alvizi Cruz
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs