Abstract
Disturbance of the epigenetic status of the H19 and KCNQ1OT1 imprinting centers of chromosome 11 and the CDKN1C imprinted gene in early human embryolethality have been studied. This is the first study to detect hypomethylation of KCNQ1OT1 in the maternal homolog in placental tissues from some (9.5%) spontaneous abortions with impaired cell proliferation during the first trimester of pregnancy. Tissue specificity of the aberrant methylation status of the imprinting center has been found. A hypothesis on the postimplantation origin of epimutations in somatic cells of the developing embryo is put forward. The selective role of epimutations of imprinted genes in early human ontogeny as compared to uniparental disomy is considered; estimation of the epigenetic risk entailed in using assisted reproductive technologies is discussed.
Similar content being viewed by others
References
Morison, I.M., Paton, C.J., and Cleverley, S.D,. The Imprinted Gene and Parent-of-Origin Effect Database, Nucl. Acids Res., 2001, vol. 29, no. 1, pp. 275–276, http://igc.otago.ac.nz/home.html
Tycko, B. and Morison, R., Physiological Functions of Imprinted Genes, J. Cell Phys., 2002, vol. 192, pp. 245–258.
Cattanach, B.M. and Jones, J., Genetic Imprinting in the Mouse: Implications for Gene Regulation, J. Inher. Metabol. Disease, 1994, vol. 17, no. 4, pp. 403–421.
Henderson, D.J., Sherman, L.S., and Loughna, S.C., Early Embryonic Failure Associated with Uniparental Disomy for Human Chromosome 21, Hum. Mol. Genet., 1994, vol. 3, no. 8, pp. 1373–1376.
Shaffer, L.G., McCaskill, C., Adkins, K., and Hassold, T.J., Systematic Search for Uniparental Disomy in Early Fetal Losses: The Results and a Review of the Literature, Am. J. Med. Genet., 1998, vol. 79, pp. 366–372.
Smith, M., Creasy, M.R., Clarke, A., and Upadhyaya, M., Sex Ratio and Absence of Uniparental Disomy in Spontaneous Abortions with a Normal Karyotype, Clin. Genet., 1998, vol. 4, pp. 258–261.
Evdokimova, V.N. and Nazarenko, S.A., The Absence of Uniparental X Chromosome Inheritance in Spontaneous Abortions with the 46,XX Karyotype, Ontogenez, 2000, vol. 31, no. 3, pp. 201–204.
Fritz, B., Aslan, M., and Kalscheuer, V., Low Incidence of UPD in Spontaneous Abortions beyond the 5th Gestational Week, Eur. J. Hum. Genet., 2001, vol. 9, pp. 910–916.
Nikitina, T.V., Sazhenova, E.A., Sukhanova, N.N., et al., Evaluation of the Role of Uniparental Disomy in Early Human Embryolethality, Ontogenez, 2004, vol. 35, no. 4, pp. 238–246.
Kondo, Y., Tsukishiro, S., Tanemura, M., et al., Maternal Uniparental Disomy of Chromosome 16 in a Case of Spontaneous Abortion, J. Hum. Genet., 2004, vol. 49, pp. 177–181.
Horsthemke, B., Epimutations in Human Disease, Curr. Top. Microbiol. Immunol., 2006, vol. 310, pp. 45–59.
Engel, J.R., Smallwood, A., Harper, A., et al., Epigenotype-Phenotype Correlations in Beckwith-Wiedemann Syndrome, J. Med. Genet., 2000, vol. 37, pp. 921–926.
Higashimoto, K., Soejima, H., Saito, T., et al., Imprinting Disruption of the CDKN1C/KCNQ1OT1 Domain: The Molecular Mechanisms Causing Beckwith-Wiedemann Syndrome and Cancer, Cytogenet. Genome Res., 2006, vol. 113, pp. 306–312.
Tycko, B., Imprinted Genes in Placental Growth and Obstetric Disorders, Cytogenet. Genome Res., 2006, vol. 113, pp. 271–278.
Li, E., Chromatin Modification and Epigenetic Reprogramming in Mammalian Development, Nat. Rev. Genet., 2002, vol. 3, pp. 662–673.
Poon, L.L., Leung, T.N., Lau, T.K., and Chow, K.C., Differential DNA Methylation between Fetus and Mother as a Strategy for Detecting Fetal DNA in Maternal Plasma, Clin. Chem., 2002, vol. 48, pp. 35–41.
Li, Y., Hirokazu, N., Ohno, T., et al., Aberrant DNA Methylation of p57 kip2 Gene in the Promoter Region in Lymphoid Malignancies of B-Cell Phenotype, Blood, 2002, vol. 100, pp. 2572–2577.
Grunau, C., Clark, S.J., and Rosenthal, A., Bisulfite Genomic Sequencing: Systematic Investigation of Critical Experimental Parameters, Nucl. Acids Res., 2001, vol. 29, no. 13, p. e65.
Kubota, T., Das, S., and Christian, L.S., et al., Methylation-Specific PCR Simplifies Imprinting Analysis, Nat. Genet., 1997, vol. 16, no. 1, pp. 16–17.
Veyver, I.B. and Al-Hussaini, T.K., Biparental Hydatidiform Moles: A Maternal Effect Mutation Affecting in the Offspring, Hum. Reprod., 2006, vol. 12, pp. 233–242.
DeBaun, M.R., Niemitz, E.L., and Feinberg, A.P., Association of in vitro Fertilization with Beckwith-Wiedemann Syndrome and Epigenetic Alterations of LIT1 and H19, Am. J. Hum. Genet., 2003, vol. 72, pp. 156–160.
Horsthemke, B. and Ludwig, M., Assisted Reproduction: The Epigenetic Perspective, Hum. Reprod. Upd., 2005, vol. 11, pp. 473–482.
Lebedev, I.N. and Puzyrev, V.P., Epigenetic Perspectives of Safety in Assisted Reproductive Technologies, Russ. J. Genet., 2007, vol. 43, no. 9, pp. 961–972.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © E.A. Sazhenova, I.N. Lebedev, 2008, published in Genetika, 2008, Vol. 44, No. 12, pp. 1609–1616.
Rights and permissions
About this article
Cite this article
Sazhenova, E.A., Lebedev, I.N. Epimutations of the KCNQ1OT1 imprinting center of chromosome 11 in early human embryolethality. Russ J Genet 44, 1394–1399 (2008). https://doi.org/10.1134/S1022795408120028
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1022795408120028