Insights into the Regulation of a Common Variant of HMGA2 Associated with Human Height During Embryonic Development
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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.
KeywordsHMGA2 Human height Embryonic stem cells microRNA miR196-b
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.
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.
Conflict of Interest
- 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.Google Scholar
- 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.
- 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle Scholar