What is epigenetics?
All cells in your body have the same DNA, yet they express different proteins and do different things. How does that happen? Various alterations in your cells affect the expression of genes, without altering their contents. This is known as epigenetics.1 Cells of different tissue types have different epigenetic alterations that lead them to produce different proteins, which allows them to fill different functions.
Once a cell has chosen its job and accumulated epigenetic alterations that lead it to produce the correct proteins, those alterations usually persist through cell division.2 This means that if a gene is deactivated in a mother cell, it will also be deactivated in both daughter cells. This allows liver cells to stay liver cells, and kidney cells stay kidney cells.3
However, as an individual ages, random errors are introduced and daughter cells stop resembling their mother cell as strongly; they may pick up new epigenetic alterations, or lose old ones. This leads to the expression of proteins inappropriate for the cell, or the loss of proteins necessary for the cell to function. Changes of this kind are known as epigenetic drift, a hallmark of aging.
Epigenetic drift contributes to a variety of diseases of aging, including cancer, Alzheimer’s disease, and bone loss. However in many cases we don’t know how epigenetics are causing problems, merely that they are. For instance, we can detect genome-wide changes in methylation, but do not know which specific genes are important to the effect. Because of this, we have only a few ideas about how to control or reverse epigenetic drift–diet and especially calories are believed to play a role, and, counterintuitively, resetting a cell all the way back to pluripotency may enable it to reacquire the epigenetic alterations it needs. Unfortunately these ideas are a long way from useful implementation.
Epigenetics and aging
The most common epigenetic changes stemming from aging are methylation (adding of methyl groups to a gene, leading to the absence of a necessary protein) or demethylation (removal of methyl groups from a gene, leading to the presence of an unwanted protein). These can have a variety of consequences. For example, methylation of tumor suppressing genes is implicated in multiple cancers, and an increase in overall methylation is associated with loss of muscle mass and heart disease. Meanwhile demethylation is also associated with cancer, by decreasing chromosomal stability,4 and with Alzheimer’s disease.
Changes in expression of microRNA can also lead to changes in proteins produced. Excess microRNA is associated with Alzheimer’s disease and loss of bone density, although the mechanism producing this excess microRNA is not clear. MicroRNAs are implicated in cancer via their role in transposon regulation.
The mechanisms of epigenetics
The addition of a methyl group to cytosine nucleotides (the C of ATCG). Methylcytosine behaves much like normal cytosine; it can bond with guanine and be transcribed into RNA. However for reasons that are not fully understood, heavily methylated regions of DNA are transcribed less often, leading to fewer copies of the proteins those genes code for. Amount of methylation can provide something of a calibration knob to let cells control how much of a particular protein they produce.
Histones are spherical proteins that DNA wraps around to form chromosomes. This wrapping must be “unwound” for transcription to take place. Modifications to the histone, which are also not well understood, can prevent this unwinding, and thus prevent transcription. This is effectively an “off” switch for the affected genes.
Traditionally RNA serves as a messenger, representing a copy of a gene that can be turned into a protein (called translation). However some DNA is transcribed into RNA that is not subsequently translated, and some of these RNA sequences regulate gene transcription. This can happen in a few different ways:
* Binding with messenger RNA by having a complementary sequence, preventing it from being translated (think of lint blocking velcro strips from attaching)
* Modifying histones or other structural components of chromosomes
* Binding with transposons5 on the chromosome to suppress them
Telomeres are generally thought of as a cell’s biological clock, telling it when it’s time to shut down. New evidence indicates that some of their power comes from up- or down-regulating genetic expression, especially but not limited to genes near the telomeres. Affected genes include ISG15 (related to immune defense against viruses), DSP (related to cardiac muscle), and C1S (also part of the immune system).
What can you do about it?
Very little, at this point in time, however there are some intriguing new therapies on the horizon.
Much of the effect of diet on health appears to be mediated through epigenetics. Scientists do not yet agree on what the healthiest diet is, and it probably varies from person to person. Severe calorie restriction in particular has been shown to reduce the epigenetic effect of time passing, probably by reducing the number of cell divisions; however this can have other consequences like reduced immune function, and is not necessarily a life extender outside the lab.
Ocampo et al crossed progeric (rapidly aging) mice with mice capable of excess expression of pluripotency genes. They then activated these genes with doxycycline, enabling them to experimentally induce expression at their desired level. Expression of Yamanaka factors led to a reversal of some age-related effects and metabolic disease in progeric mice. The fact that organisms became more functional after treatment suggests that the cells “reset” to pluripotency and then redifferentiated into their particular cell type.
Liu et al succeeded in using CRISPR to edit DNA methylation in mice. At the moment they are focused on this as a tool for studying genomics, rather than for anti-aging applications, possibly due to difficulty in getting CRISPR systems to recognize which cells to target.
Bakhoum and Compton present very preliminary data that both decreasing and increasing chromosomal stability may fight cancer. When a cell divides, chromosomes are pulled to the nucleus of their future cell by proteins called microtubules. Destabilizing the attachment between microtubules and chromosomes leads to fewer mistakes and less aneuploidy (cells with something other than exactly two copies of each chromosome). This resists cancer by reducing the variation that evolution has to work with, which gives the cancer fewer chances to evolve virulence or drug resistance. Meanwhile, increasing the stability of microtubules leads to more chromosomal errors in cell division, increasing aneuploidy. This may fight cancer by causing so much cellular damage it triggers apoptosis.
Want more? You can find a selection of articles related to this hallmark here.
- Epigenetics can also refer to heritable non-sequence changes. For example, there are certain genes whose expressions are altered depending on whether they are inherited from the mother or father. Most of these have to do with how many resources the fetus extracts from the mother: father-originating genes tend to take more than mother-originating genes. Evolutionarily, this makes sense; a mother will want to conserve her resources for future children, while the father (who may not be the father of her future children) would like the mother to spend as many resources as possible on his child. In lifelong-monogamous species this effect is much less pronounced.
- How does a cell differentiate in the first place? It depends, but one important method is Hox genes. Hox genes regulate the expression of other genes, and are regulated themselves by the presence of retinoids (vitamin A). In essence, your body has sets of genes marked “to be expressed if vitamin A is present”. Early in embryonic development a single burst of retinoids is released, designating one area of the embryo as the future head. This burst diffuses along the remainder of the embryo, telling cells their distance from the head of the embryo. Hox genes use this information to activate the genes that will enable cells to become the correct sort of proto-tissue. This is why Accutane is so dangerous during pregnancy: the megadose of vitamin A overwhelms the embryonic signalling and leads to inappropriate gene expression.
- This is a bit of a simplification. There is more than one kind of kidney or liver cell: cells within tissues are identical to one another, and organs are made up of multiple tissues.
- The relationship between chromosomal instability and cancer is complex and not fully understood, but it appears that when a cell has chromosomal abnormalities (for instance, pieces of chromosomes broken off) and it divides, its daughter cells have more variation than when a stable cell divides. The more variation present, the higher the chance a cell will have the necessary conditions for cancer–frequent divisions, resistance to apoptosis, and the ability to evade the immune system. Chromosomal variation gives evolution more “rolls of the dice” to find a cell with that configuration.
- Transposons are the ultimate parasite: regions of DNA that can cause themselves to be copied and inserted elsewhere in the genome in the same cell. This insertion can mutate needed genes and turn off others entirely; it is thus very important that an organism suppress transposons as much as possible.