Genomic imprinting: It takes two to make a thing go right

A review of: Influence of paternally imprinted genes on development. Barton SC, Ferguson-Smith AC, Fundele R, Surani MA. Development. 1991 Oct;113(2):679-87.

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Epigenetics is the modification of gene expression, without changing the DNA sequence. One epigenetic process crucial for normal development is ‘genomic imprinting.’ That is, the silencing of genes. The ‘imprint’ instructs for DNA methylation (thus directly switching genes off), and post-translational histone modifications (to alter DNA accessibility). But the really, really interesting thing about imprinting is that, unlike with most genes, it only actually affects one of the two homologous parental alleles. For instance, if the paternal allele is imprinted, then the maternal allele is the only functional copy of that gene. One way of testing imprinted gene function is by analysing their associated phenotypes, which is exactly what Sheila Barton and her colleagues did in 1991 when studying the role of paternally-imprinted genes on mouse development. They mated F1 female and male mice, collected the F2 fertilised eggs and blastocyst-stage embryos, and then used nuclear transplantation to construct androgenetic (or AG) and gynogenetic (or GG) eggs. In essence, each diploid egg contained not one, but two sets of the paternal or maternal genomes, respectively. After some culturing, the researchers isolated the inner cell mass from each egg, and injected them into blastocysts. These operated blastocysts were transferred to the female mice; after a week, some embryos were dissected out and studied, while others were left to term.

Barton found that the AG embryos were easily distinguishable from their non-AG siblings. When left to term, they exhibited severe growth abnormalities. The spine was severely scoliotic, the ribs enlarged, distorted, fused, and the heart was also enlarged and disorganised. GPI analysis confirmed that in these deformed areas, AG cell contribution was substantial. In contrast, it was especially low in the brain which, correspondingly, displayed no phenotypic change. Barton concluded that the change in shape was proportional to AG cell contribution, but levels above 50% were lethal. In contrast, GG cells cause reciprocal phenotypes with growth reduced by up to 50%, with high contributions in the brain, and low in skeletal muscle.

Barton’s data was so important because it suggested that imprinting of some parental alleles establishes a balance of gene dosage in the developing diploid embryo, and that this balance is essential for normal growth and development. The task for researchers now is to identify other imprinted genes, understand their phenotypic effects and roles during development, as well as the molecular mechanisms behind the epigenetic phenomenon that is genomic imprinting.

Creator: Elizabeth Au

References:
Barton, S. C., A. C. Ferguson-Smith, R. Fundele, and M.A. Surani, 1991 Influence of paternally imprinted genes on development. Development 113: 679-687.
Mann, J. R., and C. L. Stewart, 1991 Development of mouse androgenetic aggregation chimeras. Development 113: 1325-1333.
Paulsen, M., and A. C. Ferguson-Smith, 2001 DNA methylation in genomic imprinting, development, and disease. J. Pathol. 195: 97-110.
Surani, M.A., R. Kothary, N. D. Allen, P.B. Singh, R. Fundele, et al., 1990 Genome imprinting and development in the mouse. Dev. Suppl. 108: 89-98.
Thamban, T., V. Agarwaat, and S. Khosta, 2020 Role of genomic imprinting in mammalian development. J. Biosci. 45: 1-20.
Thomson, J. A., and D. Salter, 1988 The developmental fate of androgenetic, parthenogenetic, and gynogenetic cells in chimeric gastrulating mouse embryos. Genes. Development 2: 1344-1351.