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

Author

Listed:
  • Lucas Alvizi

    (University College London)

  • Diogo Nani

    (Universidade de Sao Paulo)

  • Luciano Abreu Brito

    (Universidade de Sao Paulo)

  • Gerson Shigeru Kobayashi

    (Universidade de Sao Paulo)

  • Maria Rita Passos-Bueno

    (Universidade de Sao Paulo)

  • Roberto Mayor

    (University College London
    Universidad Mayor)

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.

Suggested Citation

  • Lucas Alvizi & Diogo Nani & Luciano Abreu Brito & Gerson Shigeru Kobayashi & Maria Rita Passos-Bueno & Roberto Mayor, 2023. "Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38526-1
    DOI: 10.1038/s41467-023-38526-1
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