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

Author(s)

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

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 14, n. 1, p. 14-pg., 2023-05-24.

Abstract

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)

• FAPESP's process: 17/11430-7 - Interaction of genetic and epigenetic factors in response to inflammation for the predisposition to cleft lip-palate
• Grantee: Lucas Alvizi Cruz
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC