Abstract
Increasing evidence suggests that miRNA binding-site polymorphism in the 3′-untranslated region (3′UTR) of a target gene could affect that gene’s expression, and can be associated with a variety of complex traits. In this study, we find that miR-18a and cell division cycle 42 (CDC42) mRNA, whose expression was inversely correlated, are differentially expressed in porcine placentas during critical stages of placental development. rs55618224 (T>C), a SNP in the 3′UTR region of CDC42 that is perfectly complementary to the miR-18a seed could influence miR-18a-related regulation of CDC42 gene by altering their binding affinity. In addition, CDC42 mRNA was found to have higher expression level in the homozygous TT placentas as compared to those homozygous CC placentas in pigs. Furthermore, we identified a significant association between rs55618224 and total number born per litter. These results suggest the miR-18a binding-site polymorphism in CDC42 3′UTR may impact litter size by regulation of CDC42 gene in porcine placentas.
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References
Agarwal V, Bell GW, Nam J-W, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. elife 4:e05005
Ambros V (2004) The functions of animal microRNAs. Nature 431:350
An X et al (2015) Single-nucleotide polymorphisms g. 151435C> T and g. 173057T> C in PRLR gene regulated by bta-miR-302a are associated with litter size in goats. Theriogenology 83:1477–1483.e1471
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism and function. Cell 116:281–297
Bidarimath M, Tayade C (2017) Pregnancy and spontaneous fetal loss: a pig perspective. Mol Reprod Dev 84(9):856–869
Brest P et al (2011) A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet 43:242
Chang WL et al (2018) PLAC8, a new marker for human interstitial extravillous trophoblast cells, promotes their invasion migration. Development. https://doi.org/10.1242/dev.148932
Clop A et al (2006) A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38:813
Colombié N, Choesmel-Cadamuro V, Series J, Emery G, Wang X, Ramel D (2017) Non-autonomous role of Cdc42 in cell-cell communication during collective migration. Dev Biol 423:12–18
Covarrubias-Pazaran G (2016) Genome-assisted prediction of quantitative traits using the R package sommer. PLoS ONE 11:e0156744
Dantzer V (1985) Electron microscopy of the initial stages of placentation in the pig. Anat Embryol (Berl) 172:281–293
Dehapiot B, Carrière V, Carroll J, Halet G (2013) Polarized Cdc42 activation promotes polar body protrusion and asymmetric division in mouse oocytes. Dev Biol 377:202–212
Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629
Grimson A, Farh KK-H, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105
Hernandez SC, Finlayson HA, Ashworth CJ, Haley CS, Archibald AL (2014) A genome-wide linkage analysis for reproductive traits in F2 Large White x Meishan cross gilts. Anim Genet 45:191–197. https://doi.org/10.1111/age.12123
Hong L, Hou C, Li X, Li C, Zhao S, Yu M (2014) Expression of heparanase is associated with breed-specific morphological characters of placental folded bilayer between Yorkshire and Meishan pigs. Biol Reprod 90:56. https://doi.org/10.1095/biolreprod.113.114181
Hong L et al (2017) E-cadherin and ZEB2 modulate trophoblast cell differentiation during placental development in pigs. Reproduction 154:765–775. https://doi.org/10.1530/rep-17-0254
Humphreys KJ, McKinnon RA, Michael MZ (2014) miR-18a inhibits CDC42 and plays a tumour suppressor role in colorectal cancer cells. PLoS ONE 9:e112288
Krawczynski K, Najmula J, Bauersachs S, Kaczmarek MM (2015) MicroRNAome of porcine conceptuses and trophoblasts: expression profile of micrornas and their potential to regulate genes crucial for establishment of pregnancy. Biol Reprod 92:21. https://doi.org/10.1095/biolreprod.114.123588
Lee D-G, Nam J, Kim SW, Kang Y-M, An HJ, Kim CW, Choi J-S (2015) Proteomic analysis of reproduction proteins involved in litter size from porcine placenta. Biosci Biotechnol Biochem 79:1414–1421
Li H et al (2015) Integrated analysis of miRNA/mRNA network in placenta identifies key factors associated with labor onset of Large White and Qingping sows. Sci Rep 5:13074. https://doi.org/10.1038/srep13074
Li J et al (2017) Essential role of Cdc42 in cardiomyocyte proliferation and cell-cell adhesion during heart development. Dev Biol 421:271–283
Liu S, Li Q, Na Q, Liu C (2012) Endothelin-1 stimulates human trophoblast cell migration through Cdc 42 activation. Placenta 33:712–716
Liu R, Wang M, Su L, Li X, Zhao S, Yu M (2015) The expression pattern of MicroRNAs and the associated pathways involved in the development of porcine placental folds that contribute to the expansion of the exchange surface. Area Biol Reprod 93:62. https://doi.org/10.1095/biolreprod.114.126540
Ma C et al (2016) miR-762 promotes porcine immature Sertoli cell growth via the ring finger protein 4 (RNF4 gene). Sci Rep 6:32783
Maier R et al (2015) Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder. Am J Hum Genet 96:283–294
Mendell JT (2008) miRiad roles for the miR-17-92 cluster in development and disease. Cell 133:217–222
Moszyńska A, Gebert M, Collawn JF, Bartoszewski R (2017) SNPs in microRNA target sites and their potential role in human disease. Open Biol 7:170019
Nicola C, Lala PK, Chakraborty C (2008) Prostaglandin E2-mediated migration of human trophoblast requires RAC1 and CDC42. Biol Reprod 78:976–982. https://doi.org/10.1095/biolreprod.107.065433
Pirooz HJ et al (2017) Functional SNP in microRNA-491-5p binding site of MMP9 3′-UTR affects cancer susceptibility. J Cell Biochem 119(7):5126–5134
Rempel LA, Freking BA, Miles JR, Nonneman DJ, Rohrer GA, Vallet JL, Schneider JF (2011) Association of porcine heparanase and hyaluronidase 1 and 2 with reproductive and production traits in a Landrace–Duroc–Yorkshire population. Front Genet 2:20
Roy J, Mallick B (2017) Altered gene expression in late-onset Alzheimer’s disease due to SNPs within 3′ UTR microRNA response elements. Genomics 109:177–185
Shao G, Luo L, Jiang S, Deng C, Xiong Y, Li F (2011) AC/T mutation in microRNA target sites in BMP5 gene is potentially associated with fatness in pigs. Meat Sci 87:299–303
Su L, Zhao S, Zhu M, Yu M (2010) Differential expression of microRNAs in porcine placentas on days 30 and 90 of gestation. Reprod Fertil Dev 22:1175–1182. https://doi.org/10.1071/rd10046
Tak YG, Farnham PJ (2015) Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome. Epigenet Chromatin 8:57
Vallet JL, Freking BA (2007) Differences in placental structure during gestation associated with large and small pig fetuses. J Anim Sci 85:3267–3275. https://doi.org/10.2527/jas.2007-0368
Vallet JL, Miles JR, Freking BA (2009) Development of the pig placenta Soc. Reprod Fertil Suppl 66:265–279
Vallet JL, Miles JR, Freking BA (2010) Effect of fetal size on fetal placental hyaluronan and hyaluronoglucosaminidases throughout gestation in the pig. Anim Reprod Sci 118:297–309
Vallet J, McNeel A, Johnson G, Bazer F (2013) Triennial reproduction symposium: limitations in uterine and conceptus physiology that lead to fetal losses. J Anim Sci 91:3030–3040
Wang S-m, Zeng W-x, Wu W-s, Sun L-l, Yan D (2018) Association between a microRNA binding site polymorphism in SLCO1A2 and the risk of delayed methotrexate elimination in Chinese children with acute lymphoblastic leukemia. Leuk Res 65:61–66
Zhang Y, Wang Q-C, Liu J, Xiong B, Cui X-S, Kim N-H, Sun S-C (2017) The small GTPase CDC42 regulates actin dynamics during porcine oocyte maturation. J Reprod Dev 63:505–510
Zhu X-m, Han T, Sargent IL, Yin G-w, Yao Y-q (2009) Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies. Am J Obstet Gynecol 200:661.e661–661.e667
Acknowledgements
This work was funded by the Natural Science Foundation of China (31572370), Natural Science Foundation of Hubei Province (Grant# 2018CFA015), Fundamental Research Funds for the Central Universities (Program No. 2662018PY037), and HZAU pre-research project of China. The authors thank Dr. Sean Simmons from Broad institute of MIT and Harvard for helpful language modification.
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Liu, R., Deng, D., Liu, X. et al. A miR-18a binding-site polymorphism in CDC42 3′UTR affects CDC42 mRNA expression in placentas and is associated with litter size in pigs. Mamm Genome 30, 34–41 (2019). https://doi.org/10.1007/s00335-018-9788-x
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DOI: https://doi.org/10.1007/s00335-018-9788-x