IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38526-1.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38526-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-38526-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Brendan Maher, 2008. "Personal genomes: The case of the missing heritability," Nature, Nature, vol. 456(7218), pages 18-21, November.
    2. Julia K. Goodrich & Moriel Singer-Berk & Rachel Son & Abigail Sveden & Jordan Wood & Eleina England & Joanne B. Cole & Ben Weisburd & Nick Watts & Lizz Caulkins & Peter Dornbos & Ryan Koesterer & Zach, 2021. "Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Darina Czamara & Gökçen Eraslan & Christian M. Page & Jari Lahti & Marius Lahti-Pulkkinen & Esa Hämäläinen & Eero Kajantie & Hannele Laivuori & Pia M. Villa & Rebecca M. Reynolds & Wenche Nystad & Sir, 2019. "Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    4. Teri A. Manolio & Francis S. Collins & Nancy J. Cox & David B. Goldstein & Lucia A. Hindorff & David J. Hunter & Mark I. McCarthy & Erin M. Ramos & Lon R. Cardon & Aravinda Chakravarti & Judy H. Cho &, 2009. "Finding the missing heritability of complex diseases," Nature, Nature, vol. 461(7265), pages 747-753, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ruixue Fan & Shaw-Hwa Lo, 2013. "A Robust Model-free Approach for Rare Variants Association Studies Incorporating Gene-Gene and Gene-Environmental Interactions," PLOS ONE, Public Library of Science, vol. 8(12), pages 1-14, December.
    2. von Stumm, Sophie & Kandaswamy, Radhika & Maxwell, Jessye, 2023. "Gene-environment interplay in early life cognitive development," Intelligence, Elsevier, vol. 98(C).
    3. Diana Chang & Alon Keinan, 2012. "Predicting Signatures of “Synthetic Associations” and “Natural Associations” from Empirical Patterns of Human Genetic Variation," PLOS Computational Biology, Public Library of Science, vol. 8(7), pages 1-9, July.
    4. Dongjun Chung & Can Yang & Cong Li & Joel Gelernter & Hongyu Zhao, 2014. "GPA: A Statistical Approach to Prioritizing GWAS Results by Integrating Pleiotropy and Annotation," PLOS Genetics, Public Library of Science, vol. 10(11), pages 1-14, November.
    5. Noah Zaitlen & Peter Kraft & Nick Patterson & Bogdan Pasaniuc & Gaurav Bhatia & Samuela Pollack & Alkes L Price, 2013. "Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits," PLOS Genetics, Public Library of Science, vol. 9(5), pages 1-11, May.
    6. Gustavo de los Campos & Ana I Vazquez & Rohan Fernando & Yann C Klimentidis & Daniel Sorensen, 2013. "Prediction of Complex Human Traits Using the Genomic Best Linear Unbiased Predictor," PLOS Genetics, Public Library of Science, vol. 9(7), pages 1-15, July.
    7. Young Lee & Suyeon Park & Sanghoon Moon & Juyoung Lee & Robert C. Elston & Woojoo Lee & Sungho Won, 2014. "On the Analysis of a Repeated Measure Design in Genome-Wide Association Analysis," IJERPH, MDPI, vol. 11(12), pages 1-21, November.
    8. C Ryan King & Paul J Rathouz & Dan L Nicolae, 2010. "An Evolutionary Framework for Association Testing in Resequencing Studies," PLOS Genetics, Public Library of Science, vol. 6(11), pages 1-11, November.
    9. Kevin R Thornton & Andrew J Foran & Anthony D Long, 2013. "Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect," PLOS Genetics, Public Library of Science, vol. 9(2), pages 1-14, February.
    10. Zhongshang Yuan & Hong Liu & Xiaoshuai Zhang & Fangyu Li & Jinghua Zhao & Furen Zhang & Fuzhong Xue, 2013. "From Interaction to Co-Association —A Fisher r-To-z Transformation-Based Simple Statistic for Real World Genome-Wide Association Study," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-8, July.
    11. Yumei Yang & Qishan Wang & Qiang Chen & Rongrong Liao & Xiangzhe Zhang & Hongjie Yang & Youmin Zheng & Zhiwu Zhang & Yuchun Pan, 2014. "A New Genotype Imputation Method with Tolerance to High Missing Rate and Rare Variants," PLOS ONE, Public Library of Science, vol. 9(6), pages 1-7, June.
    12. Chung-Feng Kao & Jia-Rou Liu & Hung Hung & Po-Hsiu Kuo, 2015. "A Robust GWSS Method to Simultaneously Detect Rare and Common Variants for Complex Disease," PLOS ONE, Public Library of Science, vol. 10(4), pages 1-14, April.
    13. Chang Lu & Jan Zaucha & Rihab Gam & Hai Fang & Smithers & Matt E. Oates & Miguel Bernabe-Rubio & James Williams & Natalie Zelenka & Arun Prasad Pandurangan & Himani Tandon & Hashem Shihab & Raju Kalai, 2023. "Hypothesis-free phenotype prediction within a genetics-first framework," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    14. Ian Barnett & Rajarshi Mukherjee & Xihong Lin, 2017. "The Generalized Higher Criticism for Testing SNP-Set Effects in Genetic Association Studies," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 112(517), pages 64-76, January.
    15. Colin D Steer & Patrick Bolton & Jean Golding, 2015. "Preconception and Prenatal Environmental Factors Associated with Communication Impairments in 9 Year Old Children Using an Exposome-Wide Approach," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-26, March.
    16. Bingxin Zhao & Fei Zou, 2022. "On polygenic risk scores for complex traits prediction," Biometrics, The International Biometric Society, vol. 78(2), pages 499-511, June.
    17. Dominic Russ & John A Williams & Victor Roth Cardoso & Laura Bravo-Merodio & Samantha C Pendleton & Furqan Aziz & Animesh Acharjee & Georgios V Gkoutos, 2022. "Evaluating the detection ability of a range of epistasis detection methods on simulated data for pure and impure epistatic models," PLOS ONE, Public Library of Science, vol. 17(2), pages 1-19, February.
    18. Jaleal S Sanjak & Anthony D Long & Kevin R Thornton, 2017. "A Model of Compound Heterozygous, Loss-of-Function Alleles Is Broadly Consistent with Observations from Complex-Disease GWAS Datasets," PLOS Genetics, Public Library of Science, vol. 13(1), pages 1-30, January.
    19. Janet Currie, 2011. "Ungleichheiten bei der Geburt: Einige Ursachen und Folgen," Perspektiven der Wirtschaftspolitik, Verein für Socialpolitik, vol. 12(s1), pages 42-65, May.
    20. Ai-Ru Hsieh & Dao-Peng Chen & Amrita Sengupta Chattopadhyay & Ying-Ju Li & Chien-Ching Chang & Cathy S J Fann, 2017. "A non-threshold region-specific method for detecting rare variants in complex diseases," PLOS ONE, Public Library of Science, vol. 12(11), pages 1-16, November.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38526-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.