Mum vs Dad – a battle in epigenetics.

By George Young

The formation of organisms and their continued development can be attributed partly to DNA, but significant credit also lies with epigenetics. Individuals inherit epigenetic marks from their parents, and also accumulate their own epigenetic modifications in their lifetime. Study of these epigenetic marks and modifications can explore nuanced differences in traits between individuals. A key focus of epigenetic research centers on inheritance mechanisms – which, perhaps unexpectedly, involve a certain degree of genetic conflict.

Epigenetics relates to the modifications which alter the expression of DNA, generally by restricting or encouraging mRNA production. These alterations to our genetic code come in the form of several chemical structures – primarily, but not exclusively, methyl and adenyl groups. They have different uses depending on where and when they are added – a role played by enzyme families such as DNA methyltransferase (DNMT). This addition can be made on the cytosines of CpG regions, or on the histone protein around which DNA is wrapped. The former, when involving methylation, usually leads to gene repression while the latter increases genetic expression.¹

The field of epigenetics lends itself to researchers from wide-ranging biological disciplines and continues to fascinate with increasingly exciting mechanisms of gene control. One area of great interest is the contrasting influences of paternal and maternal epigenetic modifications in a developing embryo. The fundamental story behind this concept will be discussed shortly, but a slightly deeper understanding of epigenetics must first be obtained – specifically, the sub-topic of imprinting. To understand imprinting, it is necessary to grasp what happens to the epigenetic modifications in cells during gamete formation. They are almost entirely removed by demethylases, excluding a few key tags, to create a ‘blank slate’ state before a select few are re-added by methyltransferases.² The imprinted regions which are re-added depend on whether a sperm cell or oocyte is being formed. All sperm cell chromosomes need to bear the mark of a father, despite coming from an organism with both a maternal and paternal chromosome, and the same goes for the mother.

Comically coined ‘The Battle of the Sexes’ in Nessa Carey’s book The Epigenetics Revolution, the ‘competing’ imprinting from the mother and father seems to be exactly that – a kind of tug-of-war between parents who have different biological needs.^3,4 But, what exactly are they competing over? Can two homologous chromosomes not live with their different epigenetic modifications in peace? The short answer is yes – they can. They both exist with the epigenetic tags placed on them by the parent from which they are inherited, but many of these tags exist primarily to cancel out the other one’s effects on the organism to which they belong – especially during embryo development. This may feel rather counterintuitive and inefficient, but as Nessa Carey so elegantly described with her tug-of-war analogy, this phenomenon arose due to contrasting biological needs from the parents. In a short and brutal summary, the father doesn’t need the mother to survive after birthing his young, as he only needs to pass on his own genes. Likewise, the mother doesn’t care for the father’s genes, and it is her priority to survive to pass on her own to future offspring. As a result, much of the imprinting in the sperm encourages two things: maximal foetal growth with a proportionally larger head to increase foetal survival chances and a highly developed placenta to drain as many resources from the mother into the foetus as possible. On the contrary, maternal imprinting limits foetal growth to ensure practicality in birth and restricts placental over-development.

This research was fascinating but, while it has since been tested and discussed by relatively recent studies, it was conducted in the late eighties. Existing now as something of a relic of scientific information, it’s hardly an example of cutting-edge research – despite being as compelling as it was sixteen years before the human genome had even been sequenced. Nevertheless, this competition between paternal and maternal imprinting continues to offer intriguing revelations in modern research. One such advance took place in 2018, with a paper that described a new way in which paternal imprinting encourages offspring survival at the detriment of the mother.⁵ It does so by increasing the foetal expression of the Phlda2 gene, which affects the mother’s hippocampus, increasing the ‘maternal nurturing’ instinct. Thus, the mother will protect and devote resources to their offspring for longer – indirectly increasing the survival of the father’s genes.

The significance of this example lies in the stage of development in which it takes effect – after birth. It unleashed the effects of paternal imprinting across postnatal development as opposed to maintaining the pre-natal restrictions of previous research.

The examples described here represent a small fraction of the existing research, and an even smaller fraction of the potential discoveries in maternal and paternal imprinting that could be uncovered with further research. Nonetheless, they highlight the significance of epigenetics in advancing understanding of genetic inheritance and the influences that determine our traits.

References:

1. Deng G, Chen A, Hong J, Chae HS, Kim YS. Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer research. 1999; 59 (9): 2029-2023. 
2. Piccolo FM, Fisher AG. Getting rid of DNA methylation. Trends in cell biology. 2014; 24 (2): 136-143. 
3. Surani M, Barton SC, Norris ML. Influence of parental chromosomes on spatial specificity in androgenetic↔ parthenogenetic chimaeras in the mouse. Nature. 1987; 326 (6111): 395-397. 
4. Carey N. The epigenetics revolution: How modern biology is rewriting our understanding of genetics, disease, and inheritance. : Columbia University Press; 2012.
5. Creeth HD, McNamara GI, Tunster SJ, Boque-Sastre R, Allen B, Sumption L, et al. Maternal care boosted by paternal imprinting in mammals. PLoS biology. 2018; 16 (7): e2006599.