Although we have known of the interactions of nature and nurture for decades, the term 'epigenetics' has only recently been taken up by scientists and the wider public to refer to these phenomena. The Genetics Unzipped podcast, 'Pimp my Genome – The wonderful world of epigenetics', delivered by Dr Kat Arney for the Genetics Society, examines epigenetics from a historical perspective, provides examples of known epigenetic mechanisms, and highlights how fragmented and limited our understanding of the environmental factors in genetics and heredity still is.
The stage was set very well by comparing neurons and liver cells to remind the listeners that although all the cells in the body carry the same genetic code, they are not all the same, due to different regulation mechanisms. Dr Arney then introduced Conrad Waddington who coined the term 'epigenetics' in the 1940s, making the listener wonder why this has only emerged recently as a hot topic in popular science. The examples that followed begin to suggest that the complexity of epigenetic phenomena might explain this lag, as well as a dismissive attitude of scientific communities towards unexplained research observations.
Dr Arney discussed histone modifications, as the first instance of epigenetic regulation, and explained that these proteins, which serve to organise our DNA inside the nucleus, can display signs, such as 'no entry', for genes that should remain off, and 'open for business' for those genes that should be active in a particular cell type and/or in response to a specific environmental cue.
The inheritance of responses to environmental factors, referred to as transgenerational epigenetic inheritance, was then illustrated by the effects of the Dutch famine of 1944-45. This was a great example, which served not only to impress the listener with meticulous wartime record keeping, but it may also have stunned many by driving home the message that whatever our grandparents were exposed to when they were still just embryos, has the potential to influence our health today.
The developmental programming which has led to changes in the embryos' gene activities as they sensed the lack of food and other environmental stressors, affected all the cells of developing embryos during the Dutch famine, including eggs and sperm. Due to this developmental programming effect on the germ cells of the individuals conceived in Nazi-occupied Holland, their children and grandchildren will also have inherited the epigenetic changes intended to help to deal with food scarcity and starvation. Measurable effects of the famine are still observed today and include a higher risk of obesity and cardiovascular disorders, Dr Arney explains.
The concept of transgenerational epigenetic inheritance, which refers to inheritance of features independent of the genetic code, but triggered by environmental factors, was advocated by Jean-Baptiste Lamarck as early as the 19th century. Yet solid evidence for this theory has begun to emerge only recently, as revealed, for instance, by research by Dr Oliver Rando's laboratory at the University of Massachusetts, which shows that this hereditary mechanism may be mediated by the transfer of small RNA molecules.
This concept led Dr Arney to the next example of transgenerational epigenetic inheritance, namely Dr Minoo Rassoulzadegan's 'Micky Mouse Mice'. This phenotype, related to the regulation of a gene called Kit, encoding a signalling protein, resulted from one copy of Kit being active and the other one switched off. These mice had white gloves and socks on their paws and a white tail-tip, which prompted the Mickey Mouse nickname.
Dr Arney then explained that when Dr Rassoulzadegan bred the mice with each other, all the mice had white feet, even though this would have been expected for only half of the newborns, according to Mendelian inheritance laws. Even more bizarrely, crossing the Mickey Mouse mice with each other further led to many being born with even more white touches, and some being completely white. Dr Rassoulzadegan's investigations into these odd observations revealed RNA molecules in sperm cells were linked to the observed phenotypes, thus agreeing well with Dr Rando's findings about their tole in transgenerational epigenetics.
Two molecular interactions involving microRNAs were mentioned; one which alleviated the 'Mickey Mouse' effect, and another one involving a microRNA binding to a product of the Cdk9 gene. MicroRNAs have the ability to 'silence' information encoded by our DNA by binding to complementary messenger RNAs of their target genes and triggering processes like their degradation before they can be translated into proteins and resulting in, for example, pigments missing from the Mickey Mouse paws. These interactions are specific, so there is great potential for microRNA molecules to be used as tools in personalised precision medicine in the future.
As I was previously involved in functional annotation of microRNAs implicated in heart processes, it was additionally exciting for me to hear about Dr Rassoulzadegan's Cdk9-matching microRNA, linked to cardiac hypertrophy, because these findings further validate curated results from other sources. The process of functional gene annotation and curation involves extraction of experimental findings from published research articles and recording this information in a standardised manner in universally accessible databases and resources that can be used by other researchers and clinicians, for instance, for analyses of large numbers of genetic changes in a group of patients affected by a health condition.
The Dutch famine study and the Mickey Mouse investigation were brilliant examples of the value and impact of longitudinal observations on our understanding of human physiology on the one hand, and the challenging research work aiming to reveal the underlying mechanisms of the observed effects triggered by environmental factors on the other hand. The podcast beautifully demonstrated the complementarity of both approaches and the value of collaboration among research communities for charting a path towards harnessing our new knowledge for advancing precision medicine.
Dr Arney concluded by highlighting that the current evidence for microRNA transport within vesicles supports Charles Darwin's 19th century theory about 'gemmules', which he proposed were small particles originating from different body tissues and congregating in the gonads, thus affecting hereditary traits in offspring. The complementarity between the 19th century Darwin's 'gemmules' theory and Lamarck's conviction about heredity of features acquired during one's lifetime extrapolates superbly towards the Mickey Mouse and the Dutch famine examples described in this podcast. One can now only wonder how much more these great minds could have achieved had they had access to the technology and data available today!
Dr Arney explores the subject of epigenetics more fully in her book entitled: Herding Hemingway's Cats: Understanding how our genes work.