Epigenetics: phenotype inheritance beyond DNA

By Sabino Méndez Pastor

In 1953, James Watson and Francis Crick proposed the double helix model for the structure of DNA. This discovery allowed Dr Crick to define the central dogma of molecular biology as the two-step process by which the information in genes flows into proteins. This implies that phenotypes are the result of genes being transcribed into mRNA molecules which are in turn translated into proteins. However, recent discoveries have shown that this is not entirely true. Even though all cells in the human body have the same genome, there are 200 different types of them. Besides this, identical (or monozygotic) twins have the same chromosomal DNA sequence except for small errors of DNA replication but they are affected differently by genetic disorders. For example, 70%-84% of the cases schizophrenia are caused by genes inherited from the parents. Yet, only half of monozygotic twin pairs share the disease (Wong, Gottesman and Petronis, 2005). These differences could be attributed to environmental effects although the cloning of mammals has shown that there is a third component that can influence the phenotype of individuals. Clones which have the same DNA and are bred under the same conditions as the donor animals rarely exhibit the same phenotype as the donor. For instance, Tamashiro et al. (2003) showed that mice clones gained significantly more body weight as adults than control mice which were subjected to the same in vitro manipulation and culture conditions as clones but were naturally fertilized. In fact, cloned mice tended to be obese, but controls were not. But how can cells or organisms with the same genetic information exhibit different phenotypes? The answer is epigenetics. 

Epigenetics is defined as a change in gene expression maintained through cell division that does not involve a change in DNA sequence. The main epigenetic factors are DNA methylation, post-translational modifications (PTMs) of histones and non-coding RNAs (ncRNAs). DNA methylation is the covalent addition of a methyl group to a cytosine residue followed by a guanine, referred as a CpG dinucleotide. When it occurs in the promoter region of a gene, it prevents the transcription machinery from binding and silences the gene. DNA is wrapped around histones which facilitate its packaging in the nucleus. Histone tails interact to facilitate the formation of 30 nm fibres that further condense DNA. PTMs of histone tails affect DNA packaging and make gene promoters more or less accessible to transcription factors, modifying the expression of the genes wrapped around those histones. ncRNAs are RNA molecules transcribed from DNA but that do not encode for proteins. These include microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and tRNA-derived fragments. They regulate gene expression post-transcriptionally as they mostly target RNA molecules. For example, miRNAs silence genes by binding mRNA and degrading it or preventing ribosomes from binding. Epigenetic modifications are passed on during cell division, maintaining cell identity and explaining the large diversity of cell types in multicellular organisms. In addition, epigenetic factors are present in spermatozoids and oocytes therefore they can be passed from parents to the offspring and modify the phenotype of the later. 

In rodents, exposure to various environmental factors can induce epigenetic modifications. When inherited, epigenetic modifications and their consequences can be beneficial if the offspring finds a similar environment as they are better adapted. However, if the environment changes, they can be maladaptive and even cause disease in cases where there are no genetic problems. These non-genetic modifications can be established in utero and affect not only rodents throughout adult life, but also their offspring (Bohacek and Mansuy, 2015). For example, foetal caloric restriction reduces DNA methylation in rats’ primordial germ cells. The offspring of rats subjected to malnutrition show cognitive deficits such as impaired home orienting and visual discrimination, problems that persist even when the rats return for a normal diet, suggesting a link between DNA methylation and the transmission of cognitive impairment in malnourished mammals.

Besides diet, some chemicals can cause epigenetic modifications. Foetal alcohol exposure increases DNA methylation and decreases DNA hydroxymethylation at loci such as the pro-opiomelanocortin (Pomc) promoter in sperm. This has been identified as a response to addictive behaviours as in mice chronic exposure to ethanol before mating reduces ethanol preference and consumption in the male offspring. Finally, the offspring of mice exposed to chronic traumatic experiences in their early postnatal life display altered social recognition across up to three generations. This transmission could be mediated by ncRNAs as injection of sperm RNAs from male mice subjected to postnatal trauma into naturally fertilized oocytes causes the behavioural symptoms described above in mice arising from the RNA-injected eggs and in their progeny (Bohacek and Mansuy, 2015). 

Examples of potential non-genetic inheritance have also been observed in humans. As in mice, in utero exposure to famine has been associated with increased risk of disease throughout life. People conceived during the Dutch Huger Winter (1944-1945) showed decreased DNA methylation of the gene IGF2 and increased prevalence of cardiovascular disease, obesity and type II diabetes in their later life. Their offspring also displayed increased neonatal adiposity which might be the first evidence of increased obesity and diabetes risk (Painter et al., 2008). Traumatic events can also cause epigenetic modifications in humans. The adult offspring of Holocaust survivors has decreased DNA methylation of the gene coding for FK506-binding protein 5. This modification results in an altered metabolism of the stress hormone cortisol. Finally, chemicals can affect non-genetic inheritance of phenotypes in humans too. Studies on germ cell epigenetic factors revealed that the sperm of smokers had altered expression of miRNAs that regulate sperm and embryo development. Furthermore, smoking during and before pregnancy is associated with prevalence of asthma in the smokers’ grandchildren. Nevertheless, the study of epigenetic transmission in humans present limitations as there cannot be controlled experiments of a genetically homogenous population that only differs on exposure to certain factors (Senaldi and Smith-Raska, 2020). 

In conclusion, there is growing evidence suggesting that the traditional Mendelian model of inheritance which states that phenotypes are transmitted based on the transfer of DNA sequences across generations is limited. The findings described above prove that non-genetic modifications can be transmitted across generations, potentially leading better adaptation to the environment but also resulting in disease. Therefore, further studies on the precise consequences of epigenetic mutations and exploration of less known epigenetic factors such as PIWI-interacting RNAs, non-CpG methylation and protamine PTMs should help to understand the underlying mechanisms of health conditions caused by non-genetic transmission. 

References: 

Bohacek, J. and Mansuy, I. M. (2015) ‘Molecular insights into transgenerational non-genetic inheritance of acquired behaviours’, Nature Reviews Genetics. Nature Publishing Group, pp. 641–652. doi: 10.1038/nrg3964.

Painter, R. C. et al. (2008) ‘Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life’, BJOG: An International Journal of Obstetrics and Gynaecology. John Wiley & Sons, Ltd, 115(10), pp. 1243–1249. doi: 10.1111/j.1471-0528.2008.01822.x.

Senaldi, L. and Smith-Raska, M. (2020) ‘Evidence for germline non-genetic inheritance of human phenotypes and diseases’, Clinical epigenetics. NLM (Medline), p. 136. doi: 10.1186/s13148-020-00929-y.

Tamashiro, K. L. K. et al. (2003) ‘Phenotype of Cloned Mice: Development, Behavior, and Physiology’, Experimental Biology and Medicine. Society for Experimental Biology and Medicine, 228(10), pp. 1193–1200. doi: 10.1177/153537020322801015.

Wong, A. H. C., Gottesman, I. I. and Petronis, A. (2005) ‘Phenotypic differences in genetically identical organisms: The epigenetic perspective’, Human Molecular Genetics. Oxford Academic, pp. R11–R18. doi: 10.1093/hmg/ddi116.

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