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Possible effect of SNAIL family transcriptional repressor 1 polymorphisms in non-syndromic cleft lip with or without cleft palate

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Abstract

Objective

Orofacial development is a complex process subjected to failure impairing. Indeed, the cleft of the lip and/or of the palate is among the most frequent inborn malformations. The JARID2 gene has been suggested to be involved in non-syndromic cleft lip with or without cleft palate (nsCL/P) etiology. JARID2 interacts with the polycomb repressive complex 2 (PRC2) in regulating the expression patterns of developmental genes by modifying the chromatin state.

Materials and methods

Genes coding for the PRC2 components, as well as other genes active in cell differentiation and embryonic development, were selected for a family-based association study to verify their involvement in nsCL/P. A total of 632 families from Italy and Asia participated to the study.

Results

Evidence of allelic association was found with polymorphisms of SNAI1; in particular, the rs16995010-G allele was undertransmitted to the nsCL/P cases [P = 0.004, odds ratio = 0.69 (95% C.I. 0.54–0.89)]. However, the adjusted significance value corrected for all the performed tests was P = 0.051.

Conclusions

The findings emerging by the present study suggest for the first time an involvement of SNAI1 in the nsCL/P onset.

Clinical relevance

Interestingly, SNAI1 is known to promote epithelial to mesenchymal transition by repressing E-cadherin expression, but it needs an intact PRC2 to act this function. Alterations of this process could contribute to the complex etiology of nsCL/P.

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References

  1. Calzolari E, Pierini A, Astolfi G, Bianchi F, Neville AJ, Rivieri F (2007) Associated anomalies in multi-malformed infants with cleft lip and palate: an epidemiologic study of nearly 6 million births in 23 EUROCAT registries. Am J Med Genet A 143A(6):528–537. https://doi.org/10.1002/ajmg.a.31447

    Article  PubMed  Google Scholar 

  2. Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC (2009) Cleft lip and palate. Lancet 374(9703):1773–1785. https://doi.org/10.1016/S0140-6736(09)60695-4

    Article  PubMed  Google Scholar 

  3. Lidral AC, Moreno LM (2005) Progress toward discerning the genetics of cleft lip. Curr Opin Pediatr 17(6):731–739. https://doi.org/10.1097/01.mop.0000185138.65820.7f

    Article  PubMed  PubMed Central  Google Scholar 

  4. Beaty TH, Marazita ML, Leslie EJ (2016) Genetic factors influencing risk to orofacial clefts: today's challenges and tomorrow’s opportunities. F1000Res 5:2800. https://doi.org/10.12688/f1000research.9503.1

    Article  PubMed  PubMed Central  Google Scholar 

  5. Eiberg H, Bixler D, Nielsen LS, Conneally PM, Mohr J (1987) Suggestion of linkage of a major locus for nonsyndromic orofacial cleft with F13A and tentative assignment to chromosome 6. Clin Genet 32(2):129–132

    Article  PubMed  Google Scholar 

  6. Scapoli L, Pezzetti F, Carinci F, Martinelli M, Carinci P, Tognon M (1997) Evidence of linkage to 6p23 and genetic heterogeneity in nonsyndromic cleft lip with or without cleft palate. Genomics 43(2):216–220. https://doi.org/10.1006/geno.1997.4798

    Article  PubMed  Google Scholar 

  7. Scapoli L, Martinelli M, Pezzetti F, Palmieri A, Girardi A, Savoia A, Bianco AM, Carinci F (2010) Expression and association data strongly support JARID2 involvement in nonsyndromic cleft lip with or without cleft palate. Hum Mutat 31(7):794–800. https://doi.org/10.1002/humu.21266

    Article  PubMed  Google Scholar 

  8. Hao Y, Mi N, Jiao X, Zheng X, Song T, Zhuang D, Tian S, Feng D (2015) Association of JARID2 polymorphisms with non-syndromic orofacial clefts in northern Chinese Han population. J Oral Pathol Med 44(5):386–391. https://doi.org/10.1111/jop.12244

    Article  PubMed  Google Scholar 

  9. Messetti AC, Machado RA, de Oliveira CE, Martelli-Junior H, de Almeida Reis SR, Moreira HS, Persuhn DC, Wu T, Coletta RD (2017) Brazilian multicenter study of association between polymorphisms in CRISPLD2 and JARID2 and non-syndromic oral clefts. J Oral Pathol Med 46(3):232–239. https://doi.org/10.1111/jop.12470

    Article  PubMed  Google Scholar 

  10. Martinez AM, Cavalli G (2006) The role of polycomb group proteins in cell cycle regulation during development. Cell Cycle 5(11):1189–1197. https://doi.org/10.4161/cc.5.11.2781

    Article  PubMed  Google Scholar 

  11. Surface LE, Thornton SR, Boyer LA (2010) Polycomb group proteins set the stage for early lineage commitment. Cell Stem Cell 7(3):288–298. https://doi.org/10.1016/j.stem.2010.08.004

    Article  PubMed  Google Scholar 

  12. Prezioso C, Orlando V (2011) Polycomb proteins in mammalian cell differentiation and plasticity. FEBS Lett 585(13):2067–2077. https://doi.org/10.1016/j.febslet.2011.04.062

    Article  PubMed  Google Scholar 

  13. Piunti A, Pasini D (2011) Epigenetic factors in cancer development: polycomb group proteins. Future Oncol 7(1):57–75. https://doi.org/10.2217/fon.10.157

    Article  PubMed  Google Scholar 

  14. Pontier DB, Gribnau J (2011) Xist regulation and function explored. Hum Genet 130(2):223–236. https://doi.org/10.1007/s00439-011-1008-7

    Article  PubMed  PubMed Central  Google Scholar 

  15. O'Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21(13):4330–4336. https://doi.org/10.1128/MCB.21.13.4330-4336.2001

    Article  PubMed  PubMed Central  Google Scholar 

  16. Schuettengruber B, Cavalli G (2009) Recruitment of polycomb group complexes and their role in the dynamic regulation of cell fate choice. Development 136(21):3531–3542. https://doi.org/10.1242/dev.033902

    Article  PubMed  Google Scholar 

  17. Simon JA, Kingston RE (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 10(10):697–708. https://doi.org/10.1038/nrm2763

    Article  PubMed  Google Scholar 

  18. Pasini D, Cloos PA, Walfridsson J, Olsson L, Bukowski JP, Johansen JV, Bak M, Tommerup N, Rappsilber J, Helin K (2010) JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464(7286):306–310. https://doi.org/10.1038/nature08788

    Article  PubMed  Google Scholar 

  19. Shen X, Kim W, Fujiwara Y, Simon MD, Liu Y, Mysliwiec MR, Yuan GC, Lee Y, Orkin SH (2009) Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139(7):1303–1314. https://doi.org/10.1016/j.cell.2009.12.003

    Article  PubMed  PubMed Central  Google Scholar 

  20. Li G, Margueron R, Ku M, Chambon P, Bernstein BE, Reinberg D (2010) Jarid2 and PRC2, partners in regulating gene expression. Genes Dev 24(4):368–380. https://doi.org/10.1101/gad.1886410

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cooper S, Grijzenhout A, Underwood E, Ancelin K, Zhang T, Nesterova TB, Anil-Kirmizitas B, Bassett A, Kooistra SM, Agger K, Helin K, Heard E, Brockdorff N (2016) Jarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2. Nat Commun 7:13661. https://doi.org/10.1038/ncomms13661

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lin Y, Dong C, Zhou BP (2014) Epigenetic regulation of EMT: the Snail story. Curr Pharm Des 20(11):1698–1705. https://doi.org/10.2174/13816128113199990512

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tange S, Oktyabri D, Terashima M, Ishimura A, Suzuki T (2014) JARID2 is involved in transforming growth factor-beta-induced epithelial-mesenchymal transition of lung and colon cancer cell lines. PLoS One 9(12):e115684. https://doi.org/10.1371/journal.pone.0115684

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nouri N, Memarzadeh M, Carinci F, Cura F, Scapoli L, Nouri N, Jafary F, Sedghi M, Sadri L, Salehi M (2015) Family-based association analysis between nonsyndromic cleft lip with or without cleft palate and IRF6 polymorphism in an Iranian population. Clin Oral Investig 19(4):891–894. https://doi.org/10.1007/s00784-014-1305-3

    Article  PubMed  Google Scholar 

  25. Martinelli M, Girardi A, Cura F, Nouri N, Pinto V, Carinci F, Morselli PG, Salehi M, Scapoli L (2016) Non-syndromic cleft lip with or without cleft palate in Asian populations: association analysis on three gene polymorphisms of the folate pathway. Arch Oral Biol 61:79–82. https://doi.org/10.1016/j.archoralbio.2015.10.019

    Article  PubMed  Google Scholar 

  26. Koivisto AM, Ala-Mello S, Lemmela S, Komu HA, Rautio J, Jarvela I (2007) Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin Genet 72(2):145–149. https://doi.org/10.1111/j.1399-0004.2007.00836.x

    Article  PubMed  Google Scholar 

  27. Herranz N, Pasini D, Diaz VM, Franci C, Gutierrez A, Dave N, Escriva M, Hernandez-Munoz I, Di Croce L, Helin K, Garcia de Herreros A, Peiro S (2008) Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol 28(15):4772–4781. https://doi.org/10.1128/MCB.00323-08

    Article  PubMed  PubMed Central  Google Scholar 

  28. de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37(11):1217–1223. https://doi.org/10.1038/ng1669

    Article  PubMed  Google Scholar 

  29. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265. https://doi.org/10.1093/bioinformatics/bth457

    Article  PubMed  Google Scholar 

  30. Cura F, Bohmer AC, Klamt J, Schunke H, Scapoli L, Martinelli M, Carinci F, Nothen MM, Knapp M, Ludwig KU, Mangold E (2016) Replication analysis of 15 susceptibility loci for nonsyndromic cleft lip with or without cleft palate in an italian population. Birth Defects Res A Clin Mol Teratol 106(2):81–87. https://doi.org/10.1002/bdra.23454

    Article  PubMed  Google Scholar 

  31. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. https://doi.org/10.1086/519795

    Article  PubMed  PubMed Central  Google Scholar 

  32. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52(3):506–516

    PubMed  PubMed Central  Google Scholar 

  33. Kazeem GR, Farrall M (2005) Integrating case-control and TDT studies. Ann Hum Genet 69(3):329–335. https://doi.org/10.1046/J.1469-1809.2005.00156.x

    Article  PubMed  Google Scholar 

  34. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300

    Google Scholar 

  35. Mehrotra D (2015) Genomic expression in non syndromic cleft lip and palate patients: a review. J Oral Biol Craniofac Res 5(2):86–91. https://doi.org/10.1016/j.jobcr.2015.03.003

    Article  PubMed  PubMed Central  Google Scholar 

  36. Carver EA, Jiang R, Lan Y, Oram KF, Gridley T (2001) The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol 21(23):8184–8188. https://doi.org/10.1128/MCB.21.23.8184-8188.2001

    Article  PubMed  PubMed Central  Google Scholar 

  37. Noden DM (1986) Origins and patterning of craniofacial mesenchymal tissues. J Craniofac Genet Dev Biol Suppl 2:15–31

    PubMed  Google Scholar 

  38. Hay ED (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233(3):706–720. https://doi.org/10.1002/dvdy.20345

    Article  PubMed  Google Scholar 

  39. Yu W, Ruest LB, Svoboda KK (2009) Regulation of epithelial-mesenchymal transition in palatal fusion. Exp Biol Med (Maywood) 234(5):483–491. https://doi.org/10.3181/0812-MR-365

    Article  Google Scholar 

  40. Martinez-Alvarez C, Blanco MJ, Perez R, Rabadan MA, Aparicio M, Resel E, Martinez T, Nieto MA (2004) Snail family members and cell survival in physiological and pathological cleft palates. Dev Biol 265(1):207–218. https://doi.org/10.1016/j.ydbio.2003.09.022

    Article  PubMed  Google Scholar 

  41. Yu W, Zhang Y, Ruest LB, Svoboda KK (2013) Analysis of Snail1 function and regulation by Twist1 in palatal fusion. Front Physiol 4:12

    Article  PubMed  PubMed Central  Google Scholar 

  42. Murray SA, Oram KF, Gridley T (2007) Multiple functions of Snail family genes during palate development in mice. Development 134(9):1789–1797. https://doi.org/10.1242/dev.02837

    Article  PubMed  Google Scholar 

  43. Miller SF, Weinberg SM, Nidey NL, Defay DK, Marazita ML, Wehby GL, Moreno Uribe LM (2014) Exploratory genotype-phenotype correlations of facial form and asymmetry in unaffected relatives of children with non-syndromic cleft lip and/or palate. J Anat 224(6):688–709. https://doi.org/10.1111/joa.12182

    Article  PubMed  PubMed Central  Google Scholar 

  44. Song H, Wang X, Yan J, Mi N, Jiao X, Hao Y, Zhang W, Gao Y (2017) Association of single-nucleotide polymorphisms of CDH1 with nonsyndromic cleft lip with or without cleft palate in a northern Chinese Han population. Medicine (Baltimore) 96(5):e5574. https://doi.org/10.1097/MD.0000000000005574

    Article  Google Scholar 

  45. Martinelli M, Carinci F, Morselli PG, Caramelli E, Palmieri A, Girardi A, Riberti C, Scapoli L (2011) Evidence of LEF1 fetal-maternal interaction in cleft lip with or without cleft palate in a consistent Italian sample study. Int J Immunopathol Pharmacol 24(2_suppl):15–19. https://doi.org/10.1177/03946320110240S204

    Article  PubMed  Google Scholar 

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Acknowledgements

We are indebted to the families participating in the study for their invaluable contribution, as well as to all the personnel involved in clinical data and specimen collection.

Funding

This work was supported in part by a grant from the Association Interethnos Interplast Italy and by Fondazione Del Monte di Bologna e Ravenna (for the salary of Dr. Ambra Girardi).

Author information

Author notes

  1. Francesca Cura and Annalisa Palmieri contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Belmeloro, 8, 40126, Bologna, Italy

    Francesca Cura, Annalisa Palmieri, Ambra Girardi, Paolo Giovanni Morselli, Furio Pezzetti, Luca Scapoli & Marcella Martinelli

  2. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

    Francesco Carinci

  3. Plastic Surgery Unit, Sant’Orsola Malpighi University Hospital, Bologna, Italy

    Paolo Giovanni Morselli

  4. Department of Genetics and Molecular Biology, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran

    Nayereh Nouri

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  1. Francesca Cura
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  2. Annalisa Palmieri
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  3. Ambra Girardi
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  4. Francesco Carinci
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  5. Paolo Giovanni Morselli
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  6. Nayereh Nouri
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  7. Furio Pezzetti
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  8. Luca Scapoli
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  9. Marcella Martinelli
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Corresponding author

Correspondence to Marcella Martinelli.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

This investigation collected evidence supporting a possible effect of SNAI1 polymorphisms in nsCL/P etiology.

Luca Scapoli and Marcella Martinelli have shared senior authorship.

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Cura, F., Palmieri, A., Girardi, A. et al. Possible effect of SNAIL family transcriptional repressor 1 polymorphisms in non-syndromic cleft lip with or without cleft palate. Clin Oral Invest 22, 2535–2541 (2018). https://doi.org/10.1007/s00784-018-2350-0

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  • DOI: https://doi.org/10.1007/s00784-018-2350-0

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