Fundamental shifts in the way we understand our world and ourselves are rare, and when they do happen it is often with uproar. When discovery of the DNA double helix by James Watson and Francis Crick in 1953 showed us that all of nature was bound together by a common molecular mechanism, it was assumed that the information held by the DNA sequence would be the primary determinant in the biology of any organism. After the last forty years of biological research and the completion of the human genome sequence a decade ago, the overwhelming realization is that the information contained in the DNA sequence alone is only a fraction of the total information needed to animate the cell, coordinate multicellular behavior, and orchestrate life’s unfathomably complex sequence of biological events. While the discovery that layers of information beyond DNA sequence are equally important to life is in many ways as fundamental a revelation as the discovery of DNA, it has not received such widespread recognition. This is surprising, considering that there are medical implications from choice of diet to cancer treatment. Epigenetics, as this fascinating range of mechanisms is called, deserves your attention and imagination because for the foreseeable future this new paradigm will be behind advances in our understanding of multicellularity, genome-environment interaction, and human disease.
All of the cells in your body have the same genetic code, and hence the same set of instructions, but carry out drastically different functions. This begs several questions. How does a cell know which instructions to carry out? How can the genetic instructions of a cell or an organism respond to their environment? How can some cells become cancerous while others remain healthy? The answers to these questions lie in the differences in epigenetic information between cells. The Greek prefix epi-means “above” or “in addition to”, and epigenetics refers to the layers of information superimposed on top of the genetic information contained in DNA sequence. If your genetic code gives you your individual identity, epigenetics gives each of your cells their own identity. Thus, any organism is a manifestation not only of its genetic content, but also of the sum total of its epigenetic states.
The term epigenetics dates back to 1942, before the discovery of DNA [1], but it has taken sixty years of biology to describe how it works on the molecular level. To understand why epigenetics is distinct from “regular” genetics, posing a new set of challenges and fundamentally altering the way we perceive biological information, we must get into the gritty details of DNA and its multitude of partners.
DNA, by itself, does not do anything. It is chemically inert, and the information it contains is only relevant when accessed by proteins and RNA machinery. The central idea of epigentics is perhaps that the genomic information is not just a jumble of sequence to be read in a linear manner: the information is finely organized through a series of overlayed mechanisms that control how that information is utilized.
The first level of epigenetic regulation and higher order genome structure is the way in which strands of DNA are packaged by proteins called histones. Imagine a string (the DNA) being wound around a hockey puck (the histone). These string-wrapped hockey pucks (protein-DNA complexes) are bundled into a solenoid-like pattern, which are then wrapped into even larger strands called chromatin, which make up whole chromosomes. Chromatin is the basic structure of the genome in a cellular context, but it is not all in a uniform state. Some regions are tightly packed together, which means genes in those regions are turned off, while others are less tightly packed and the genes inside can be turned on. Strands of DNA can be chemically modified by addition of a single carbon atom (methylation), which causes chromatin to pack together more tightly, leading to repression of that area of the genome [2]. Think of it as making the string stickier. The clumps of hockey pucks would be hard to unwrap.
The second level is the behavior of the histones themselves. For the string of DNA to be read by the transcriptional machinery, the hockey pucks must slide away or be removed to allow proteins to bind to the DNA. The behavior of histones, and therefore the transcriptional status of a gene, is modulated by chemical modifications that cause the hockey pucks of the histones to move further away from one another and expose the DNA string, or clump together and conceal it. Patterns of these modifications are closely related to levels of gene expression, and it appears that cells have an epigenetic “histone code” of sorts, adding another layer of information with strong consequences for cellular activity and development [3].
The third level of epigenetic regulation occurs on a larger scale. The vast majority of your genome is full of long repeats, remnants of erstwhile genes, and a hefty portion of viruses that encountered us at some ancient point in evolutionary history and decided to stay. Most of this is hardly transcribed, if at all, but it must be managed in a way that does not interfere with the active regions of the genome. This leads to a non-random ordering of the genome within the nucleus, and of regions within the same chromosome [4]. Active regions clump together, and inactive regions are repressed in a common space [5]. The spatial organization of the genome is a problem of third-order complexity, and today it is unclear what functional consequences these arrangements have. However, recent work shows that genome organization is to some degree cell-type specific, and changes during development [6].
These regulatory mechanisms, along with others such as the surprisingly varied role of RNA, comprise a rich network of information that influences cellular and organismal behavior in profound ways. Epigenetic mechanisms explain why two individuals with extremely similar genome sequence can have different physical characteristics. Identical twins have identical genomes, and are epigenetically identical at birth, but as they age, different environmental factors cause their methylation and histone modification profiles diverge, and they end up with differing patterns of gene expression and disease [7]. These changes arise within a single lifetime, but some epigenetic traits can be inherited across generations. For example, the diet of pregnant mothers can change DNA methylation patterns in the fetus, which may lead to various diseases later in life for their children [8].
Epigenetic approaches to therapy are showing promise as well, particularly in cancer, where both genetic and epigenetic profiles are drastically altered. The FDA has approved the drug decitabine, which inhibits enzymes that methylate DNA. Aberrant methylation patterns are a hallmark of several blood cancers, including acute myeloid leukemia, where decitabine has shown the most success [9]. Inhibitors of histone-modifying enzymes have also been approved for treating cancer of immune cells. Unfortunately, the complexity and redundancy of methylation and histone modifications makes it difficult to use single inhibitors of epigenetic machinery. For unknown reasons they are most effective in blood cancers, but have little effect on solid tumors. It seems that epigenetic therapies will have the most benefit when they are used in combination with one another and as supplemental therapy for more decisive interventions like bone marrow transplants or radiation therapy [10].
But there’s still the question: why should you care about epigenetics? Most importantly, epigenetics has opened new approaches to treating disease, and is promising to unleash the power of personalized medicine that sequence information alone was unable to provide. It also unravels the connections between our environment and our genomes, and provides a mechanism for how our experiences can feed back into our genetic identity. Lastly, it has redefined our understanding of how biological information is stored, processed, and transmitted. Together, these advances constitute a profound shift in how we conceptualize life, and are the foundation for the next century of biology and medicine. That is certainly worthy of an uproar.
References:
- Waddington, CH. The epigenotype. Endeavour. 1942;1:18–20.
- Bird, A. DNA mehtylation patterns and epigenetic memory. Genes & Dev. 2002;16:6-21.
- Jenuwein T, Allis CD. Translating the histone code. Science. 2001 Aug;293(5532):1074-80.
- Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326(5950):289-93.
- Misteli T. Beyond the sequence: cellular organization of genome function. Cell. 2007;128:787-800.
- Rajapaske I, Groudine M. On emerging nuclear order. JCB. 2011;192(5):711-721.
- Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102(30):10604-10609.
- Heijmans B, Tobi EW, Stein AD, Putter H, Blauw GJ, SUsser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. . Proc Natl Acad Sci USA. 2008:105(44);17046-17049.
- Claes B, Buysschaert I, Lambrechts D. Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy. Heredity. 2010;105(1):152-60.
- Thurn KT, Thomas S, Moore A, Munster PN. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol. 2011;7(2):263-83.
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