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Insights into the Regulation of a Common Variant of HMGA2 Associated with Human Height During Embryonic Development

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Abstract

Early genetic studies in the mouse and chicken identified the HMGA oncogene as a candidate that regulates body height. Subsequent genome-wide SNP studies revealed a significant association of rs1042725 genotypes CT and CC in the 3’ UTR of HMGA2 with human height. Together, these studies indicated that HMGA2 expression levels during prenatal development might be a critical factor that contributes to the height phenotype. In the present study, we sought to gain insight into the regulation of HMGA2 during human embryonic development and provide evidence that the rs1042725 genotype is unlikely to affect HMGA2 levels in pluripotent human embryonic stem cells (hESCs). This implies that hESCs in the inner cell mass of blastocysts are most likely not involved in determining the human height phenotype associated with this SNP. By applying a computational approach and cell-based reporter assays, we then identified miR-196b as a candidate microRNA that could contribute to SNP-specific expression of HMGA2 during human prenatal development. We briefly discuss this result in the context of other known functions for miR-196b during vertebrate development.

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References

  1. Chau, K. Y., Patel, U. A., Lee, K. L., Lam, H. Y., & Crane-Robinson, C. (1995). The gene for the human architectural transcription factor HMGI-C consists of five exons each coding for a distinct functional element. Nucleic Acids Research, 23, 4262–4266.

    Article  CAS  PubMed  Google Scholar 

  2. Reeves, R., & Beckerbauer, L. (2001). HMGI/Y proteins: flexible regulators of transcription and chromatin structure. Biochimica et Biophysica Acta-Gene Structure and Expression, 1519, 13–29. doi:10.1016/S0167-4781(01)00215-9.

    Article  CAS  Google Scholar 

  3. Pfannkuche, K., Summer, H., Li, O., Hescheler, J., & Dröge, P. (2009). The High Mobility Group Protein HMGA2: A Co-Regulator of Chromatin Structure and Pluripotency in Stem Cells? Stem Cell Reviews and Reports; in press.

  4. Gattas, G. J., Quade, B. J., Nowak, R. A., & Morton, C. C. (1999). HMGIC expression in human adult and fetal tissues and in uterine leiomyomata. Genes Chromosomes Cancer, 25, 316–322. doi:10.1002/(SICI)1098-2264(199908)25:4<316::AID-GCC2>3.0.CO;2-0.

    Article  CAS  PubMed  Google Scholar 

  5. Li, O., Vasudevan, D., Davey, C. A., & Droge, P. (2006). High-level expression of DNA architectural factor HMGA2 and its association with nucleosomes in human embryonic stem cells. Genesis, 44, 523–529. doi:10.1002/dvg.20242.

    Article  CAS  PubMed  Google Scholar 

  6. Li, O., Li, J., & Droge, P. (2007). DNA architectural factor and proto-oncogene HMGA2 regulates key developmental genes in pluripotent human embryonic stem cells. FEBS Letters, 581, 3533–3537. doi:10.1016/j.febslet.2007.06.072.

    Article  CAS  PubMed  Google Scholar 

  7. Fusco, A., & Fedele, M. (2007). Roles of HMGA proteins in cancer. Nature Reviews Cancer, 7, 899–910. doi:10.1038/nrc2271.

    Article  CAS  PubMed  Google Scholar 

  8. Zhou, X., Benson, K. F., Ashar, H. R., & Chada, K. (1995). Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature, 376, 771–774. doi:10.1038/376771a0.

    Article  CAS  PubMed  Google Scholar 

  9. Chieffi, P., Battista, S., Barchi, M., Di Agostino, S., Pierantoni, G. M., Fedele, M., et al. (2002). HMGA1 and HMGA2 protein expression in mouse spermatogenesis. Oncogene, 21, 3644–3650.

    Article  CAS  PubMed  Google Scholar 

  10. Battista, S., Fidanza, V., Fedele, M., Klein-Szanto, A. J., Outwater, E., Brunner, H., et al. (1999). The expression of a truncated HMGI-C gene induces gigantism associated with lipomatosis. Cancer Research, 59, 4793–4797.

    CAS  PubMed  Google Scholar 

  11. Ruyter-Spira, C. P., Herbergs, J., Limpens, E., Marsh, J. A., Van der Poel, J. J., Ayoubi, T. A., et al. (1998). Nucleotide sequence of the chicken HMGI-C cDNA and expression of the HMGI-C and IGF1 genes in autosomal dwarf chicken embryos. Biochimica et Biophysica Acta, 1399, 83–87. doi:10.1016/S0167-4781(98)00101-8.

    CAS  PubMed  Google Scholar 

  12. Ligon, A. H., Moore, S. D., Parisi, M. A., Mealiffe, M. E., Harris, D. J., Ferguson, H. L., et al. (2005). Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. American Journal of Human Genetics, 76, 340–348. doi:10.1086/427565.

    Article  CAS  PubMed  Google Scholar 

  13. Weedon, M. N., Lango, H., Lindgren, C. M., Wallace, C., Evans, D. M., Mangino, M., et al. (2008). Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genetics, 40, 575–583. doi:10.1038/ng.121.

    Article  CAS  PubMed  Google Scholar 

  14. Lettre, G., Jackson, A. U., Gieger, C., Schumacher, F. R., Berndt, S. I., Sanna, S., et al. (2008). Identification of ten loci associated with height highlights new biological pathways in human growth. Nature Genetics, 40, 584–591. doi:10.1038/ng.125.

    Article  CAS  PubMed  Google Scholar 

  15. Sanna, S., Jackson, A. U., Nagaraja, R., Willer, C. J., Chen, W. M., Bonnycastle, L. L., et al. (2008). Common variants in the GDF5-UQCC region are associated with variation in human height. Nature Genetics, 40, 198–203. doi:10.1038/ng.74.

    Article  CAS  PubMed  Google Scholar 

  16. Buysse, K., Reardon, W., Mehta, L., Costa, T., Fagerstrom, C., Kingsbury, D. J., et al. (2009). The 12q14 microdeletion syndrome: additional patients and further evidence that HMGA2 is an important genetic determinant for human height. European Journal of Medical Genetics, 52, 101–107. doi:10.1016/j.ejmg.2009.03.001.

    Article  PubMed  Google Scholar 

  17. Mari, F., Hermanns, P., Giovannucci-Uzielli, M. L., Galluzzi, F., Scott, D., Lee, D., et al. (2009). Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis. European Journal of Human Genetics, doi:10.1038/ejhg.2009.27.

  18. Droge, P., & Davey, C. A. (2008). Do cells let-7 determine stemness? Cell Stem Cell, 2, 8–9. doi:10.1016/j.stem.2007.12.003.

    Article  CAS  PubMed  Google Scholar 

  19. Hammond, S. M., & Sharpless, N. E. (2008). HMGA2, microRNAs, and stem cell aging. Cell, 135, 1013–1016. doi:10.1016/j.cell.2008.11.026.

    Article  CAS  PubMed  Google Scholar 

  20. Miranda, K. C., Huynh, T., Tay, Y., Ang, Y. S., Tam, W. L., Thomson, A. M., et al. (2006). A pattern-based method for the identification of microRNA-target sites and their corresponding heteroduplexes. Cell, 126, 1203–1217. doi:10.1016/j.cell.2006.07.031.

    Article  CAS  PubMed  Google Scholar 

  21. Tay, Y., Zhang, J., Thomson, A. M., Lim, B., & Rigoutsos, I. (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 45, 1124–1128. doi:10.1038/nature07299.

    Article  Google Scholar 

  22. Makeyev, E. V., Zhang, J., Carrasco, M. A., & Maniatis, T. (2007). The microRNA miR-124 promotes neuronal differentiation by trigerring brain-specific alternative pre-mRNA splicing. Molecular Cell, 27, 435–448. doi:10.1016/j.molcel.2007.07.015.

    Article  CAS  PubMed  Google Scholar 

  23. Mansfield, J. H., Harfe, B. D., Nissen, R., Obenauer, J., Srineel, J., Chaudhuri, A., et al. (2004). MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nature Genetics, 36, 1079–1083. doi:10.1038/ng1421.

    Article  CAS  PubMed  Google Scholar 

  24. Thermann, R., & Hentze, M. W. (2007). Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation. Nature, 447, 875–878. doi:10.1038/nature05878.

    Article  CAS  PubMed  Google Scholar 

  25. Shell, S., Park, S. M., Radjabi, A. R., Schickel, R., Kistner, E. O., Jewell, D. A., et al. (2007). Let-7 expression defines two differentiation stages of cancer. Proceedings of the National Academy of Sciences of the United States of America, 104, 11400–11405. doi:10.1073/pnas.0704372104.

    Article  CAS  PubMed  Google Scholar 

  26. Mayr, C., Hemann, M. T., & Bartel, D. P. (2007). Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science, 315, 1576–1579. doi:10.1126/science.1137999.

    Article  CAS  PubMed  Google Scholar 

  27. Hornstein, E., Mansfield, J. H., Yekta, S., Hu, J. K., Harfe, B. D., McManus, M. T., et al. (2005). The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature, 438, 671–674. doi:10.1038/nature04138.

    Article  CAS  PubMed  Google Scholar 

  28. Morin, R. D., O'Connor, M. D., Griffith, M., Kuchenbauer, F., Delaney, A., Prabhu, A. L., et al. (2008). Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. Genome Research, 18, 610–621. doi:10.1101/gr.7179508.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Singapore Academic research council (ARC) [grant number 90/07] and the National Medical Research Council (NMRC) [grant number 1114/2007] (PD), and SBIC-SSCC RPC-001/2007 (S.A.) We thank T. Stojanov and J. Shaft for advice and the provision of samples of SIVF hES cell lines.

Author Contributions

Y.T. performed qRT-PCR and miR analyses; S.P. performed genotyping and Western analyses; I. R. performed miR predictions; P.B. performed hES cell culture and genomic DNA preparation; S.H. supervised research; P.D. designed and supervised research, analyzed data, and wrote the paper.

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Authors and Affiliations

  1. Neural Stem Cells, Institute of Medical Biology, Agency for Science Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore, 138648, Singapore

    Yvonne Tay & Sohail Ahmed

  2. Division of Genomics and Genetics, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore

    Sabrina Peter & Peter Dröge

  3. Bioinformatics and Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, PO Box 218, New York, 10598, USA

    Isidore Rigoutsos

  4. Sydney IVF, 321 Kent Street, Sydney, 2000, Australia

    Paulette Barahona

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  1. Yvonne Tay
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  2. Sabrina Peter
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  3. Isidore Rigoutsos
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  4. Paulette Barahona
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  5. Sohail Ahmed
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  6. Peter Dröge
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Correspondence to Peter Dröge.

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Yvonne Tay and Sabrina Peter have contributed equally to this work.

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Tay, Y., Peter, S., Rigoutsos, I. et al. Insights into the Regulation of a Common Variant of HMGA2 Associated with Human Height During Embryonic Development. Stem Cell Rev and Rep 5, 328–333 (2009). https://doi.org/10.1007/s12015-009-9095-8

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