The Body’s Library

How the Epigenome Regulates our Genes

  • © FLI/Nadine Grimm© FLI/Nadine Grimm
  • © FLI/Nadine Grimm
  • Fig. 1: Schematic representation of DNA methylation and histone packaging as the main epigenetic regulators of gene activation. If methyl groups are added at the gene’s starting point (promoter), the gene is blocked for activation. Vice versa, if the promoter is accessible, the gene can be activated and hence, gene products like e.g. proteins can be produced. DNA is also protected from activation if the histones, around which the DNA is wrapped, are located closely next to each other. If the packaging is loosened, genes become accessible. © FLI
  • Dr. Francesco Neri

Why don’t identical twins look the same? Why do famines either lead to a higher risk for diseases or an extended lifespan? Why do some kinds of stress make us ill, and others do not? All of these questions can be reduced to one common denominator: The variable readability of our DNA – the so-called epigenome. Just like a library, it regulates who has access at which time to which information. The epigenome enables the development of complex life forms, but is also the source of many diseases.

Each cell in our body contains the building plan of our entire body. It is encoded in our DNA and consists of single genes, which regulate particular individual attributes. Gene accessibility and thus activation, however, is strictly regulated in order to guarantee that in each body tissue only tissue-specific cells, with pre-determined characteristics, are generated. Regulation of gene accessibility is mediated by a complex DNA structural organization (called chromatin) and by chemical modifications of this chromatin, which, in total, are called “the epigenome”. Simply, the epigenome is our body’s library; it categorizes the available genetic information, making only particular parts of it accessible. One example of such a chemical modification is so-called DNA methylation – a process by which methyl groups are enzymatically added to genes, thus blocking these genes for activation (fig.1). Recent studies further suggest that methyl groups not only block genes for transcription, but also serve as a marker of a gene’s start (so-called promoter) [1]. Another epigenetic mechanism for regulating gene activation is the wrapping of the DNA around protein structures, so-called histones: tightly packed, genes with sensitive information are protected from being read and activated. To have them transcribed, the packaging has to be loosened enzymatically.

Alterations During Life

Similar to the DNA, the epigenome undergoes changes during life. The process of adding methyl groups may fail or happen at the wrong genes; some genes may be spuriously activated; or DNA strands are no longer correctly and closely wrapped around histones.

Especially in older age, this may cause the improper accessibility of information, leading to a loss of organ maintenance and tissue functionality. Furthermore, the risk of suffering from diseases like cancer is rising steeply. This may happen if in cancer cells, those genes which normally hinder proliferation (so-called tumor suppressor genes) are blocked by DNA methylation. Numerous studies provide evidence that intestinal and blood (hematopoietic) stem cells are the cells where cancer most likely originates. Hence, colorectal cancer and leukemia are the most common and most fatal cancers and occur more frequently the older we get.
A new study clearly illustrates, how strongly humans are affected by epigenetic changes during aging. More than 10 per cent of humans aged 70 or older show epigenetic alterations in their hematopoietic stem cells (HSC). These stem cells accumulate epigenetic damages that provide them with a growth advantage, leading to the colonization of the hematopoietic system – so-called “clonal dominance”. It is not yet clear why and how mutated stem cells gain such an advantage. What is known is that the risk of these patients dying within the next eight years is increased by 40% [2], while their risk of suffering from leukemia is 13 times (!) higher than in patients without epigenetic changes in HSC [3]. These results are particularly astonishing, since they offer an insight into the future aging process way before any symptoms occur.

In addition, epigenetic changes also seem to affect the regenerative capacity of muscles during aging. For example in mice, gene “Hoxa9” – which is actually only important during embryonic development and is de-activated afterwards – is suddenly re-activated in old muscle stem cells after injury, which strongly decreases the muscle’s regenerative potential. Obviously, in this case information becomes accessible that under normal conditions would forever remain under lock and key [4].

Against this background, so-called “Epigenetics” – the science of analyzing the epigenome – is becoming increasingly important in aging research. Indeed, it yields hope – in contrast to genetic mutations, epigenetic alterations can be chemically reversed, offering a possible future target for therapies fighting cancer or other age-related diseases.

External Influences

In recent years, a number of studies produced evidence that external influences affecting the body may also lead to epigenetic changes. In particular, nutrition and psychosocial stress are said to cause alterations in gene activation. In bees, for example, it is only nutrition that decides whether a bee larva will become a queen or a worker [5]. In rats, it has been shown that in pups whose mothers had a reduced social binding behavior, the hormonal stress tolerance was considerably impaired [6].

In humans, external influencing factors seem to have their greatest impact on further development if they occur in early childhood. In children that survived the Hongerwinter (Dutch famine) during World War II, the risk of suffering from severe obesity in their later years is above average [7]. On the other hand, the offspring of people who survived periods of hunger and food shortage show a prolonged lifespan – indicating that epigenetic changes can be hereditary [8]. Babies whose mothers don’t hug them regularly show a delayed biological development, which may be linked to health impairments in later life [9]. Moreover, many psychological and psychiatric diseases are also linked to epigenetic alterations [10]. The list of external factors influencing our epigenome is an extensive one and includes smoking, alcohol abuse, inflammation, the composition of our microbiome, or environmental factors like radiation. However, concrete insights into the mechanisms and strength of influence have yet to be established in most cases.

Technological Challenge

Albeit, there is a simple explanation for this: The epigenetic analysis of adult stem cells represents a huge technological challenge. For one thing, it is really difficult to separate adult stem cells from the surrounding tissue to, then, analyze the whole genome for abnormal changes. Especially in intestinal cells, this is only barely working. Secondly, the number of adult stem cells in human tissues is comparatively low. Thankfully, several technological developments in recent years have enabled researchers to analyze the methylation profile of single cells. However, to do so the entire genome – with around 3 billion base pairs – needs to be analyzed using the next generation DNA sequencing; developed after the turn of the millennium, this is a novel technology and one of the most expensive methodologies in biomedicine. Another obstacle is the amount of data needed to investigate changes in chromatin modifications. In order to get a complete overview, many different types of analysis are required.

Future Outlook

While the deciphering of the human genome has led to the rapid development of genetics as a research discipline, epigenetics are still in their infancy. Genetics “just” analyze one human genome (an enormously complex task in itself); whereas epigenetics deal with individual changes that are as diverse as humans are. A lot of effort and time will be required during the upcoming years to study the epigenome of different cell types and tissues, both in health and during disease and aging. But this effort seems to offer promise: The epigenome is responsible for cells retaining their tissue-specific identity; this is why methods to regulate the epigenome will play an important role in future conventional, regenerative, and individual medicine, as well as in cancer therapy.

Already, the composition of chemotherapies is optimized by analyzing epigenetic markers, because medication often targets particular epigenetic alterations. A current study further shows that drugs intended to erase dangerous epigenetic alterations in tumor cells also seem to stimulate the production of aberrant gene transcripts. These transcripts activate hidden regulatory elements in the DNA which are able to stimulate the immune system – a surprising side effect that could even increase the future therapeutical effectivity of epigenetic treatments [11]. In addition, study results point out that by analyzing the epigenome of blood stem cells, an individual’s biological age can be measured and compared with chronological age as defined by birthday – a possible starting point for the development of preventive measures to maintain or reinstate health [12]. In the not too distant future, it may be normal to develop personalized and patient-specific medical treatments by means of epigenetic analyses, thus taking a further step towards a long and healthy life.

Summary: Medical Doctors as Librarians

Epigenetics is a promising research field that will deliver a wealth of new insights into biological processes in the coming years. Once current technological obstacles have been overcome, analyzing epigenetic changes will enable future medicine to understand disease processes individually and to develop patient-specific therapies. If we take the image of the epigenome as the body’s library, then medical doctors will become the librarians – the trusted keepers that maintain system and order in the library of life.

Author
Francesco Neri

CV
Francesco Neri, PhD, was awarded the renowned Sofia Kovalevskaja Award of the Alexander von Humboldt Foundation in 2016. With the prize money, he has built a Junior Research Group on “Epigenetics of Aging” at Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, Germany. The molecular biologist, who grew up in Siena, Italy, studied molecular biology in his hometown before completing his PhD in biotechnology. Following research stays in Nijmegen (Netherlands) and Turin (Italy), he has been at the FLI since the summer of 2016.

Contact
Dr. Francesco Neri

Junior Group Leader on “Epigenetics of Aging“
Leibniz Institute on Aging
Fritz Lipmann Institute
Jena, Germany
francesco.neri@leibniz-fli.de
www.leibniz-fli.de
 

References:

[1] Neri F, Rapelli S, Krepelova A, Incarnato D, Parlato C, Basile G, Maldotti M, Anselmi F, Oliviero O. Intragenic DNA methylation prevents spurious transcription initiation. Nature 2017, 543(7643): 72-77. DOI: 10.1038/nature21373

[2] Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 2014, 371: 2488-2498. 10.1056/NEJMoa1408617

[3] Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Chambert K, Mick E, Neale BM, Fromer M, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 2014, 371: 2477-2487. DOI: 10.1056/NEJMoa1409405

[4] Schwörer S, Becker F, Feller C, Baig AH, Köber U, Henze H, Kraus JM, Xin B, Lechel A, Lipka DB, Varghese CS, Schmidt M, Rohs R, Aebersold R, Medina KL, Kestler HA, Neri F, von Maltzahn J, Tümpel S, Rudolph KL. Epigenetic stress responses induce muscle stem cell aging by Hoxa9 developmental signals. Nature 2016, 540(7633): 428-432. DOI: 10.1038/nature20603

[5] Chittka A, Chittka L. Epigenetics of Royalty. PLoS Biol 2010, 8(11): e1000532. DOI: 10.1371/journal.pbio.1000532

[6] Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. Epigenetic programming by maternal behavior. Nat Neurosci. 2004, 7(8): 847-54. DOI: 10.1038/nn1276

[7] Ahmed F. Tales of Adversity, Nature 2010, 468: 20. DOI: 10.1038/468S20a

[8] Bygren LO, Kaati G, Edvinsson S. Longevity determined by paternal ancestors’ nutrition during their slow growth period. Acta Biotheoretica 2001, 49(1): 53-59. DOI: 10.1023/A:1010241825519 

[9] Moore SR, McEwen LM, Quirt J, Morin A. Epigenetic correlates of neonatal contact in humans. Development and Psychopathology 2017, 29(5): 1517-1538. DOI: 10.1017/S0954579417001213 

[10] Roth TL. Epigenetic mechanisms in the development of behavior: advances, challenges, and future promises of a new field. Dev Psychopathol. 2013, 25(4, Pt 2): 1279-1291. DOI: 10.1017/S0954579413000618 

[11] Brocks D, Schmidt CR, Daskalakis M, Jang HS, Shah NM, Li D, Li J, Zhang B, Hou Y, Laudato S, Lipka DB, Schott J, Bierhoff H, Assenov Y, Helf M, Ressnerova A, Islam MS, Lindroth AM, Haas S, Essers M, Imbusch CD, Brors B, Oehme I, Witt O, Lübbert M, Mallm JP, Rippe K, Will R, Weichenhan D, Stoecklin G, Gerhäuser C, Oakes CC, Wang T, Plass C. DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nature Genetics 2017 (Epub ahead of print, June 12). DOI: 10.1038/ng.3889 

[12] Petkovich DA, Podolskiy DI, Lobanov AV, Lee SG, Miller RA, Gladyshev VN. Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions. Cell Metab. 2017, 25(4): 954–960.e6. DOI: 10.1016/j.cmet.2017.03.016

 

F. Neri interviewed by Radio F.R.E.I.

Simple overview on epigenetics

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