Epigenetics: Breakthrough or BUST
There has been a rise in papers published via scientific journals and commercial news sources investigating the subject of epigenetics. The fundamental mechanics to how it impacts our day to day lives have been and continue to be investigated. There has even been a movement so to speak, centered on your ability to alter your own DNA through epigenetics, and thus not limit you to your genetic fate. This is based largely on a misconception of epigenetic mechanisms that I will get into later.
To understand the common misconception surrounding this epigenetics, you need to first understand 2 very important topics. First, the central dogma of biology, DNA makes RNA and RNA makes Protein. The process of going from DNA to RNA is transcription. Second, epigenetics plays a role in dictating what parts of your genome undergo transcription. This piece will answer two big questions, what is epigenetics, and how does it impact our lives?
Central Dogma of Molecular Biology
What is epigenetics and what does it involve?
There is at least 5 decades’ worth of research addressing this question that would take months to read. Fortunately, I have started this process for you and I am here to give a quick overview, with a fairly pleasant scientific vocabulary that won’t require an encyclopedia.
Let’s begin by breaking the question into two because the answer may be different depending on who you ask. A traditional geneticist will likely say “Epigenetics” is the study of the heritable changes in gene expression that do not have to do with the DNA sequence. “…Heritable changes in gene expression” it’s important to note that these changes are not a result of changing the DNA sequence, but changing the architecture of DNA from a topological, or structural, aspect. Meaning, how DNA molecules are positioned to each other and how that relative position affects its function. Epigenetics affects the expression by changing the way DNA is packaged, which changes how it can be accessed by enzymes known as polymerases. These polymerases are the enzymes that read the information of DNA and transcribe it into RNA.
A molecular biologist might say that “Epigenetics” is the study of mechanisms that coordinate gene expression in a cell, such as chemical signatures (covalent modifications), chromatin modifying enzymes and histone protein interactions amongst other things. This explanation is focused more on the players that mediate gene expression and less on the inheritance aspect. I personally think that this explanation is indicative of the study of chromatin biology, but I’ll get to that soon.
Moving forward, let’s fuse these two perspectives together along with some background information to create a functioning definition for “Epigenetics” in this conversation. Your DNA is principally wrapped around a group of proteins called “Histones” that help to organize and compact DNA inside of our cells.
More Importantly, when DNA is wrapped around these histones, whether or not the genetic information is expressed has to do with the molecular state of these histone proteins. What do I mean by the molecular state? Histone proteins have long amino acid tails that mediate their functional roles at any given time. Depending on how these tails are modified at specific locations, dictates in part how genomic information is accessed and the level of gene expression as a whole. These modifications are covalent in nature and come in a few flavors. Acetylation, phosphorylation, ubiquitination, and methylation are the most common forms of covalent modification for histones. These modifications change the way the histones interact with other proteins and the DNA wrapped around them.
In addition to the three-dimensional interactions resulting from DNA being wrapped around histones (which is called a nucleosome) and the molecular states of histone tails, Cytosine, one of the DNA nucleotides, methylation also deters expression of genes. Methylation of cytosine at CpG islands (Cytosine and Guanine dinucleotides), which predominately reside in the promoters of genes, deter activation of those genes. Methyl groups are non-polar, meaning they do not contribute to electrochemical interactions related to charge or polarity. When electrochemical interactions are the tool being used for two or more molecules to come together, a good way to reduce their ability to interact is to modify the chemistry promoting the interaction in the first place. Therefore, DNA methylation deters gene activation, it blocks the enzymes and proteins that bind to DNA sequences from interacting with it. Also, a difference in the topology is created, so that changes the way molecules fit together, which in turn changes the way proteins interact with DNA to activate genes.
Promoters are DNA sequences that allow for genes to be activated or silenced. These special sequences in front of genes allow for control of the genes. Methylation of nucleotides in the promoter can impact gene expression in the ways mentioned above. To illustrate Epigenetics’ fundamental role in allowing, or prohibiting gene expression, I have prepared a wonderful explanation/analogy for gene expression in the ensuing paragraph.
Genes are simply not just “on” or “off”, active or inactive at any given time. Genes can be at 0 and 100, and anywhere in between in regards to their expression (level of transcription). What is more accurate in the context of biological function, is how long a gene has been active and how active the gene is. This simply means how many transcripts have been produced from that sequence to make proteins in a given amount of time and for how long. This context is important because a gene’s ultimate goal is to produce a functioning protein. There is a caveat, much of the human genome is devoted to non-coding RNA, including microRNAs, tRNAs, siRNAs and regulatory sequences. About 30 years ago, this was considered “Junk DNA”, epigenetics plays a role in how these stretches of DNA are transcribed as well. So, the activity of a gene correlates in part to the concentration of the protein it produces. There are other downstream events that affect protein concentration, but for now, let us keep things at the transcriptional level.
Let me reference this to a light bulb and a dimmer that controls it. The dimmer turns the light on and off, but more importantly, it controls how bright that light is at any given time. The ability of the dimmer to control the brightness of the light and the dimness is analogous to the level of transcription or expression of a given gene within a cell. Epigenetics is a functioning part of the “Dimmer”, a multifaceted mechanism of coordinating expression, that is also heritable from cell to cell, and from parent to offspring. Epigenetics is not the only coordinator of expression, there are many functional parts to the “Dimmer”, including transcription factors, remodeling enzymes, and regulatory elements which are DNA sequences that promote or deter gene expression. There are many players in the symphony of epigenetic regulation. For the sake of narrowing the focus of this conversation, we won’t delve into the other instruments of this symphony. Epigenetics above all, creates the window of opportunity for these other regulatory mechanisms to function on a gene’s expression at any given time, by recruitment of other factors that activate or repress gene expression.
Now that we know what epigenetics is and what it involves, let’s get to part two of this piece. Is this an important research topic and will it tell us important information about our lives and disease? Short answer, YES! Epigenetics is important, it is a fundamental biological process that helps govern how our cells control the accessibility of their genetic information.
What does the study of epigenetics tell us?
Rather, the more valued question to most of us is, what does this research tell us about our health and disease? Since epigenetics plays a key role in how cells activate and silence genes during development, that became an obvious place to look for cancer cell transformation (oncogenesis). It was reported in a Nature study that a loss of a chromatin remodeling enzyme SMARCB1, an enzyme that alters how histones and DNA interact, resulted in an aggressive form of childhood cancer (Andrew P. Feinberg, 2015). It was later confirmed in a series of epigenetic cancer studies that alterations in DNA methylation and altered epigenetic signatures were drivers of cancer formation (Ruddon, 2007). Since then, even more, defined mechanisms between epigenetic control and cancer progression have been elucidated. Aside from its role in cancer, there have been studies looking at the role of epigenetics in conditions ranging from obesity to mental health. Ultimately, the more we know about the role epigenetics plays in disease and our health, the easier it will be to find solutions in the form of treatments and unique biomarkers for clinical diagnosis.
The Woo: You are in control of changing your DNA
So how does epigenetics affect our health? This is where the Woo (pseudoscience bullshit) starts to develop. Here is where the actual science gets distorted. An old study in mice showed that pups that were groomed more frequently had better temperaments as adult mice. Makes sense right? If you give your child hugs and affection maybe that decreases their likelihood of being an asshole, someone please reference such a study if it exists in the comments below. What was really interesting is when researchers looked at these mice, the pups that were groomed more often had different epigenetic signatures as adults than their less groomed counterparts. This means grooming, an external stimulus modified the molecular marks on histone proteins that led to changes in gene expression, which resulted in the observed better temperament by researchers. Learn more of this example here.
What this means, is that an external stimulus, (i.e. the environment around you and your own habits) can impact epigenetic signatures over time. These changes acquired over time to the epigenome can be passed on to offspring, and that’s the big picture. Here is the pseudoscience disclaimer!! You have no way of knowing what actions or external stimulus, over any time-period effect any epigenetic signature. YOU ARE NOT IN CONTROL. The Woo mills (online pseudoscience websites) of health disinformation will have you believe that you somehow have the ability to dictate gene expression of you own genes at will, and you are in control of the way epigenetics impacts your health. A good example of this flawed perspective is in this Natural News article. So, can we change or genetic destiny of certain genes at our will? Nope, negative, zilch, naught, nada, we simply are not in control of dictating our own gene expression, no matter what your subconscious thoughts are. That doesn’t mean we aren’t in control of harmful environmental stimuli, like bathing in gasoline, or smoking. It means, playing basketball or meditating isn’t going to methylate histone 3 on lysine 27 every time you do it, for everyone, at any given gene loci. We are still trying to figure out the links between epigenetic changes and environmental stimulus, but one thing is for certain, it is definitely not at our whim.
It’s not only the Woo sites that are responsible for peddling this narrative, plenty of researchers have embellished the conclusions of the role epigenetics plays in some diseases. It is one thing to notice a difference in epigenetic signatures at a gene location during a study, but without knowing what those exact changes mean in the context of the cell, or an organism, it becomes really hard to make solid conclusions. A New York Times article was recently published highlighting and warning about embellished conclusions. As a graduate student focused on epigenetic research as it pertains to disease, we need to be mindful of overarching conclusions. The solution to any disease is to find out what the problem is and develop a way to solve it. Correlations between epigenetic signatures and disease tell us where to look next, the hard part is understanding the mechanics. Fortunately, Science and all its genius lab minions are up for the challenge.
Andrew P. Feinberg, M. A. (2015). Epigenetic modulators, modifiers, and mediators in cancer etiology and progression. Nature reviews: Cancer, 284.
Ewan Birney, G. D. (2016). Epigenome-wide Association Studies and the Interpretation of Disease -Omics. PLOS Genetics, 1-9.
Goldberg, A. D., Allis, C. D., and Bernstein, E., (2007). Epigenetics: A landscape takes shape. Cell 128:635–638.
Ruddon, R. (2007). Cancer Biology. New York: Oxford University Press.
Weaver, I.C.G, Cervoni, N., Champagne, F.A., D’Alessio, A.C., Sharma, S., Seckl, J.R., Dymov, S., Szyf, M., & Meaney, M. (2004).Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847-854