Skip to main content

Advertisement

Log in

Relevance of genomic imprinting in intrauterine human growth expression of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 imprinted genes

  • Epigenetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To study the relationship of imprinted gene expression (CDKN1C, H19, IGF2, KCNQ1 and PHLDA2) with human fetal growth.

Methods

RNA was extracted from fetuses with intrauterine growth restriction (IUGR) and from the controls without growth restriction. The gene expression pattern of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 genes was evaluated using RT-PCR. MS-MLPA was also performed to assess the IC1 and IC2 DNA methylation status on chromosome 11p15.5.

Results

The samples were divided according to their tissue type in placental or fetal tissue. Within each group, IUGR cases and controls were compared. In the IUGR cases, in both fetal and placental tissue groups IGF2 was observed to be down regulated. In another approach, the samples were divided in IUGR and control groups and for each of them placental and fetal tissue was compared. Within the IUGR group up regulation of CDKN1C, KCNQ1, and PHLDA2 was determined in placental samples. IUGR group presented a statistically lower methylation status in both IC1 and in IC2. Regarding differences between fetal and placental samples within this group, methylation status of placental samples was statistically significant down regulated in the imprinting center 1 (IC1).

Conclusions

Genomic imprinting is a phenomenon that plays an important role in fetal and placental development. This study emphasizes the importance of imprinted genes during pregnancy. Differences between tissues could reflect different mechanisms, either compensatory or adverse, that should be investigated in more detail.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Snijders RJ, Sherrod C, Gosden CM, Nicolaides KH. Fetal growth retardation: associated malformations and chromosomal abnormalities. Am J Obstet Gynecol. 1993;168(2):547–55.

    Article  PubMed  CAS  Google Scholar 

  2. Ishida M, Moore GE. The role of imprinted genes in humans. Molecular aspects of medicine. 2012. doi:10.1016/j.mam.2012.06.009.

  3. Constancia M, Kelsey G, Reik W. Resourceful imprinting. Nature. 2004;432(7013):53–7. doi:10.1038/432053a.

    Article  PubMed  CAS  Google Scholar 

  4. Neerhof MG. Causes of intrauterine growth restriction. Clin Perinatol. 1995;22(2):375–85.

    PubMed  CAS  Google Scholar 

  5. St-Pierre J, Hivert MF, Perron P, Poirier P, Guay SP, Brisson D et al. IGF2 DNA methylation is a modulator of newborn’s fetal growth and development. Epigenetics : official journal of the DNA Methylation Society. 2012;7 (10).

  6. Cerrato F, Sparago A, Di Matteo I, Zou X, Dean W, Sasaki H, et al. The two-domain hypothesis in Beckwith-Wiedemann syndrome: autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster. Hum Mol Genet. 2005;14(4):503–11. doi:10.1093/hmg/ddi047.

    Article  PubMed  CAS  Google Scholar 

  7. Riccio A, Cubellis MV. Gain of function in CDKN1C. Nat Genet. 2012;44(7):737–8. doi:10.1038/ng.2336.

    Article  PubMed  CAS  Google Scholar 

  8. Jacob KJ, Robinson WP, Lefebvre L. Beckwith-Wiedemann and Silver-Russell syndromes: opposite developmental imbalances in imprinted regulators of placental function and embryonic growth. Clin Genet. 2013;84(4):326–34. doi:10.1111/cge.12143.

    Article  PubMed  CAS  Google Scholar 

  9. Ishida M, Monk D, Duncan AJ, Abu-Amero S, Chong J, Ring SM, et al. Maternal inheritance of a promoter variant in the imprinted PHLDA2 gene significantly increases birth weight. Am J Hum Genet. 2012;90(4):715–9. doi:10.1016/j.ajhg.2012.02.021.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Edwards CA, Ferguson-Smith AC. Mechanisms regulating imprinted genes in clusters. Curr Opin Cell Biol. 2007;19(3):281–9. doi:10.1016/j.ceb.2007.04.013.

    Article  PubMed  CAS  Google Scholar 

  11. Chiesa N, De Crescenzo A, Mishra K, Perone L, Carella M, Palumbo O, et al. The KCNQ1OT1 imprinting control region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases. Hum Mol Genet. 2012;21(1):10–25. doi:10.1093/hmg/ddr419.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Priolo M, Sparago A, Mammi C, Cerrato F, Lagana C, Riccio A. MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment. European journal of human genetics : EJHG. 2008;16(5):565–71.

    Article  PubMed  CAS  Google Scholar 

  13. Schneider E, Pliushch G, El Hajj N, Galetzka D, Puhl A, Schorsch M, et al. Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns. Nucleic Acids Res. 2010;38(12):3880–90. doi:10.1093/nar/gkq126.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods (San Diego, Calif). 2001;25(4):402–8. doi:10.1006/meth.2001.1262.

    Article  CAS  Google Scholar 

  15. Guo L, Choufani S, Ferreira J, Smith A, Chitayat D, Shuman C, et al. Altered gene expression and methylation of the human chromosome 11 imprinted region in small for gestational age (SGA) placentae. Dev Biol. 2008;320(1):79–91. doi:10.1016/j.ydbio.2008.04.025.

    Article  PubMed  CAS  Google Scholar 

  16. McMinn J, Wei M, Schupf N, Cusmai J, Johnson EB, Smith AC, et al. Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta. 2006;27(6–7):540–9. doi:10.1016/j.placenta.2005.07.004.

    Article  PubMed  CAS  Google Scholar 

  17. Antonazzo P, Alvino G, Cozzi V, Grati FR, Tabano S, Sirchia S, et al. Placental IGF2 expression in normal and intrauterine growth restricted (IUGR) pregnancies. Placenta. 2008;29(1):99–101. doi:10.1016/j.placenta.2007.06.010.

    Article  PubMed  CAS  Google Scholar 

  18. Apostolidou S, Abu-Amero S, O'Donoghue K, Frost J, Olafsdottir O, Chavele KM. Elevated placental expression of the imprinted PHLDA2 gene is associated with low birth weight. Journal of molecular medicine (Berlin, Germany). 2007;85(4):379–87. doi:10.1007/s00109-006-0131-8.

    Article  CAS  Google Scholar 

  19. Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, et al. Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci U S A. 2004;101(21):8204–8. doi:10.1073/pnas.0402508101.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Doria S, Sousa M, Fernandes S, Ramalho C, Brandao O, Matias A, et al. Gene expression pattern of IGF2, PHLDA2, PEG10 and CDKN1C imprinted genes in spontaneous miscarriages or fetal deaths. Epigenetics : official journal of the DNA Methylation Society. 2010;5(5):444–50.

    Article  CAS  Google Scholar 

  21. Piedrahita JA. The role of imprinted genes in fetal growth abnormalities. Birth defects research Part A, Clinical and molecular teratology. 2011;91(8):682–92. doi:10.1002/bdra.20795.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Bobetsis YA, Barros SP, Lin DM, Weidman JR, Dolinoy DC, Jirtle RL, et al. Bacterial infection promotes DNA hypermethylation. J Dent Res. 2007;86(2):169–74.

    Article  PubMed  CAS  Google Scholar 

  23. Begemann M, Spengler S, Kanber D, Haake A, Baudis M, Leisten I, et al. Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues. Clin Genet. 2011;80(1):83–8. doi:10.1111/j.1399-0004.2010.01514.x.

    Article  PubMed  CAS  Google Scholar 

  24. Azzi S, Rossignol S, Steunou V, Sas T, Thibaud N, Danton F, et al. Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet. 2009;18(24):4724–33. doi:10.1093/hmg/ddp435.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sofia Dória.

Additional information

Capsule Imprinting genes play a very important role in IUGR and methylation or gene expression levels may identify pregnancies at high risk of severe IUGR

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table 2

(DOC 120 kb)

Table 3

(DOC 176 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cordeiro, A., Neto, A.P., Carvalho, F. et al. Relevance of genomic imprinting in intrauterine human growth expression of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 imprinted genes. J Assist Reprod Genet 31, 1361–1368 (2014). https://doi.org/10.1007/s10815-014-0278-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-014-0278-0

Keywords

Navigation