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A RESEARCH ON GENOMIC IMPRINTING

Genomic imprinting is the epigenetic phenomenon mostly occurring in gametogenesis. It has independently evolved in flowering plants and mammals. In both organisms, imprinting occurs in the embryo-nourishing tissues; the endosperm and the placenta respectively. Imprinting genes regulate the transfer of nutrients to developing progeny (Beery & Workman, 2011).The genomic imprinting usually occurs when both the maternal and the paternal alleles are present but one allele expresses itself while the other remains inactive ( Engel, N. 2015). Gene imprinting is believed to be important in regulation of growth in embryo and neonate

Experiments on androgenotes and gynogenotes , which are produced by nuclear transplantation, are used to create basis of genomic imprinting. The zygotes from androgenotes and gynogenotes were formed but neither type could undergo more development. From this situation, it is possible to suggest that the maternal and paternal effects are complimentary(Morgan, Li, & O’Neill, 2009). Each genome contains different viable and necessary properties. Another evidence that genomic imprinting has a major role in growth and development comes from a research by Li et al(1993).

Optimal method for gene imprinting is DNA methylation, which is carried out with enzyme DNA methyltransferase in mammals. DNA MTase acts on the DNA sequence 5’-6pG-3’. Primarily higher eukaryotes have CpG islands in their genomes. The islands are hardly methylated in the animal cells, this could be due to the bound transcription factors that block DNA MTase. Those sequences which are methylated are normally not active. Some research also show that methylated sequences can be active (Madek, 1974).

The importance of DNA methylation was demonstrated in the study of mammalian development(Li et al, 1993). They postulated that if mutation was introduced to the DNA MTase gene in embryonic stem cell of a mice, methylation of CpG would be abnormal and the gene expression would be affected (“DNA methylation and demethylation dynamics,” 2015). Gene mutation of DNA MTase was caused by homologous recombination and Southern blot analysis affirmed this (Wilkins, 2010). The genes used were insulin-like growth factors; H19, lgf2 and lgf2 receptor; lgf2r.

Normally H19 gene, whih is a maternal allele, is expressed while the paternal allele is inactive. Inactive paternal allele is methylated but the maternal allele is not; this should be noted carefully. RNase and Northern blot analysis essays procedures demonstrated the effects of decreased levels of DNA methylation on mutant mice. It was brought to light that typical DNA methylation is a requirement to keep for the paternal allele inactive for the H19 gene (Mightiness of science, 2016)

The lgf2 is opposite of the H19 gene in that it is expressed only in a methylated paternal allele. As a result, it is expressed in mice having deficient MTase activity. It is expected that the lgf2 gene will be repressed, while the paternal allele remains unmethylated. Analysis of 9 day-old embryos using RNase protection essay examined expression of lgf2 and cytoplasmic action. Northern blots revealed that in homozygous DNA MTase mutants, lgf2 was undetectable. From the findings, it was concluded that a normal level of DNA methylation is needed for expression of the paternal lgf2 allele.

The gene lgf2r is expressed from a methylated maternal allele. Predictions were made and found out that MTase-deficient mutants alleles expressed lgf2r at some level as wild type alleles. It was suspected by Li et al that the lgf2r gene was significantly less affected by demethylation of genomic DNA but not independent of it. In order to test this, second MTase deficient mutant was created that had a deletion downstream from the first mutant’s deletion. The second deletion caused deficiencies so severe that embryos died at day 10, forming only 5-10 somites. RNase protection analysis indicated that the second mutant repressed the expression of the lgf2r gene completely. The effects of DNA demethylation on maternal lgf2r allele are substantially less significant than those of demethylation of the paternal lgf2 allele.

Genomic imprinting has implications in embryonic and extra-embryonic growth and development in a variety of organisms. Many experiments have agreed to this including Li et al’s research. To date, 50 imprinting genes have been identified in the human genome. The genes tend to be clustered together in imprinted chromosomal domains. The domains have s been mapped to chromosomes 7q32, 11p15, 15q11 and 20q13. The cluster of genes are characterized by cis regulation via IC.

According to AC Smith-2007, dysregulation of this gene cluster is associated with overgrowth and tumor predisposition syndrome, Beckwith-Wiedemann syndrome. The disruption of imprinted gene expression can result from genetic or epigenetic alteration. The genetic alteration such as duplication, deletion, translocation, inversion and mutation in imprinted regions have been shown to cause disease (Committee, Research, & Organization, 2002). Epimutations that are extrinsic to the primary DNA sequence have also been shown to cause diseases. Recently, several human diseases in addition to Beckwith-Wiedemann syndrome have been reported to have molecular alterations at chromosome 11p15.5. The diseases include Russell-silver syndrome and transient neonatal diabetes mellitus Sluckin, W., & Sluckin, W. (1973). Imprinting and early learning (2nd ed.). Chicago: Methuen.

Mackay et al (49) suggested that methylation defects at more than one locus can modify the clinical presentation of the TNDM phenotype. Most of TNDM patients presenting with lose of methylation at KCNQ1OT1 DMR have macroglossia and abdominal wall defects commonly seen in BWS patients (Shomu’s Biology, 2015)

REFERENCES

1. Engel, N. (2015). Genomic imprinting in mammals—memories of the generations past. Epigenetic Gene Expression and Regulation, 43-61. doi:10.1016/b978-0-12-799958-6.00003-2

2. Morgan, H. D., Li, Y., & O’Neill, C. (2009). 127. EPIGENETIC REPROGRAMMING IN ZYGOTES INVOLVES THE GLOBAL CYTOSINE DEMETHYLATION OF BOTH THE PATERNAL AND MATERNAL GENOMES. Reproduction, Fertility and Development, 21(9), 46. doi:10.1071/srb09abs127

3. Madek, B. E. H. (1974). Sequences of methylated T1 plus pancreatic ribonuclease products. Journal of Molecular Biology, 88(1), 158–164. doi:10.1016/0022-2836(74)90301-5

4. DNA methylation and demethylation dynamics (2015). Oncotarget. doi:10.18632/oncotarget.6039

5. Beery, T. A., & Workman, L. M. (2011). Genetics and genomics in nursing and health care. Philadelphia: F.A. Davis Company.

6. Wilkins, J. F. (2010). GENOMIC IMPRINTING AND CONFLICT-INDUCED DECANALIZATION.Evolution, 65(2), 537–553. doi:10.1111/j.1558-5646.2010.01147.x

7. Mightiness of science (2016, August 11). Genomic imprinting Retrieved from https://youtu.be/b7J2gW-GqTw

8. Shomu’s Biology (2015, August 30). Genomic imprinting Retrieved from https://youtu.be/6xvsyJNphHo

9. Committee, the A., Research, H., & Organization, W. H. (2002). Genomics and world health: Report of the advisory committee on health research. Geneva: World Health Organization.

10. Sluckin, W., & Sluckin, W. (1973). Imprinting and early learning (2nd ed.). Chicago: Methuen.