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神经嵴 E-钙黏蛋白缺失通过促炎基因-环境相互作用的表观遗传调节导致唇腭裂。

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

机构信息

Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.

Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil.

出版信息

Nat Commun. 2023 May 24;14(1):2868. doi: 10.1038/s41467-023-38526-1.

DOI:10.1038/s41467-023-38526-1
PMID:37225711
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10209087/
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.

摘要

基因-环境相互作用被认为在多因素表型中起作用，尽管其机制描述得很差。唇裂/腭裂（CLP）是最常见的颅面畸形，与遗传和环境因素都有关，尽管有少量基因-环境相互作用的实验证据。在这里，我们研究了携带不完全外显率的 CDH1/E-钙黏蛋白变异的 CLP 家族，并探讨了促炎条件与 CLP 的关联。通过研究来自小鼠、非洲爪蟾和人类的神经嵴（NC），我们表明 CLP 可以通过双打击模型来解释，其中 NC 迁移受到遗传（CDH1 功能丧失）和环境（促炎激活）因素的组合的损害，导致 CLP。最后，使用体内靶向甲基化测定，我们证明 CDH1 高甲基化是促炎反应的主要靶点，也是 E-钙黏蛋白水平和 NC 迁移的直接调节剂。这些结果揭示了颅面发育过程中的基因-环境相互作用，并提供了一种双打击机制来解释唇裂/腭裂的发病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/82894d9a5400/41467_2023_38526_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/9109f1fc2a9c/41467_2023_38526_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/4b03a9e27223/41467_2023_38526_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/38b2b178f11d/41467_2023_38526_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/e8f855451922/41467_2023_38526_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/200c36045ae4/41467_2023_38526_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/c56a034e2876/41467_2023_38526_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/82894d9a5400/41467_2023_38526_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/9109f1fc2a9c/41467_2023_38526_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/4b03a9e27223/41467_2023_38526_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/38b2b178f11d/41467_2023_38526_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/e8f855451922/41467_2023_38526_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/200c36045ae4/41467_2023_38526_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/c56a034e2876/41467_2023_38526_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf97/10209087/82894d9a5400/41467_2023_38526_Fig7_HTML.jpg

相似文献

[1]
Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene-environment interaction.

Nat Commun. 2023-5-24

[2]
Cleft lip/palate and hereditary diffuse gastric cancer: report of a family harboring a CDH1 c.687 + 1G > A germline mutation and review of the literature.

Fam Cancer. 2019-4

[3]
Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.

J Med Genet. 2006-2

[4]
Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.

Am J Hum Genet. 2018-5-24

[5]
Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate.

Hum Mutat. 2015-11

[6]
The clf2 gene has an epigenetic role in the multifactorial etiology of cleft lip and palate in the A/WySn mouse strain.

Birth Defects Res A Clin Mol Teratol. 2011-8

[7]
Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects.

Sci Rep. 2017-5-26

[8]
Current concepts on cleft lip and palate etiology.

J Biol Regul Homeost Agents. 2019

[9]
Altered regulation of cell migration in IRF6-mutated orofacial cleft patients-derived primary cells reveals a novel role of Rho GTPases in cleft/lip palate development.

Cells Dev. 2021-6

[10]
Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1.

Genet Med. 2017-3-16

引用本文的文献

[1]
Gene-by-Environment Interactions Involving Maternal Exposures with Orofacial Cleft Risk in Filipinos.

Genes (Basel). 2025-7-25

[2]
Genetic Determinants of Leukocyte Count in Nonsyndromic Cleft Lip With or Without Cleft Palate Among Asians.

Int Dent J. 2025-7-3

[3]
Sirt6 loss activates Got1 and facilitates cleft palate through abnormal activating glycolysis.

Cell Death Dis. 2025-3-6

[4]
Polarity and migration of cranial and cardiac neural crest cells: underlying molecular mechanisms and disease implications.

Front Cell Dev Biol. 2025-1-6

[5]
NSAID-mediated cyclooxygenase inhibition disrupts ectodermal derivative formation in axolotl embryos.

bioRxiv. 2025-2-15

[6]
Piezo2 interacts with E-cadherin in specialized gastrointestinal epithelial mechanoreceptors.

J Gen Physiol. 2024-12-2

本文引用的文献

[1]
Normal Table of Xenopus development: a new graphical resource.

Development. 2022-7-15

[2]
Modeling Early Neural Crest Development via Induction from hiPSC-Derived Neural Plate Border-like Cells.

Methods Mol Biol. 2022

[3]
Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis.

Acta Pharm Sin B. 2022-2

[4]
Role of Maternal Infections and Inflammatory Responses on Craniofacial Development.

Front Oral Health. 2021-9-6

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The double-edged sword role of TGF-β signaling pathway between intrauterine inflammation and cranial neural crest development.

FASEB J. 2022-1

[6]
Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun. 2021-6-9

[7]
Identification of a novel TP63 mutation causing nonsyndromic cleft lip with or without cleft palate.

BMC Med Genomics. 2021-2-23

[8]
E-cadherin focuses protrusion formation at the front of migrating cells by impeding actin flow.

Nat Commun. 2020-10-26

[9]
Genes and environments, development and time.

Proc Natl Acad Sci U S A. 2020-9-22

[10]
deficiency interacts with hypoxia and induces a morphogenetic regulation during mouse lip development.

Development. 2020-6-24

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