UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Alvizi, Lucas; Nani, Diogo; Brito, Luciano Abreu; Kobayashi, Gerson Shigeru; Passos-Bueno, Maria Rita; Mayor, Roberto; (2023) Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene-environment interaction. Nature Communications , 14 (1) , Article 2868. 10.1038/s41467-023-38526-1. Green open access

[thumbnail of Alvizi_Neural crest E-cadherin loss drives cleft lip_VoR.pdf]
Preview
PDF
Alvizi_Neural crest E-cadherin loss drives cleft lip_VoR.pdf - Published Version

Download (10MB) | Preview

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.

Type: Article
Title: Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene-environment interaction
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-023-38526-1
Publisher version: https://doi.org/10.1038/s41467-023-38526-1
Language: English
Additional information: © 2023 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Humans, Animals, Mice, Gene-Environment Interaction, Cleft Lip, Neural Crest, Cleft Palate, Cadherins, Epigenesis, Genetic
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10171059
Downloads since deposit
35Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item