The Epigenetic Revolution

2011 marks the 10th anniversary of the completion of the Human Genome Project. In this 10 years much has been added to the immense wealth of known data about As, Gs, Ts and Cs that make up our most intimate map. Though something else’s been going on, too. Ten years and still not as much control, deep knowledge as we’d like about how all those genes articulate, interact and sustain life or precipitate illness and, ultimately, death.
What’s the matter? Well, complexity, for one. It’s not just the sheer amount of data and its astounding intricacy. It’s that we still have to figure out, after the what, the how of the genome.
For decades, scientists worked under the assumption of the “one gene, one protein” dogma. It didn’t last. Alternative splicing poured new light over the genome and so we knew that there was more than one way of transcribing a gene, that there was a sort of syntax to DNA. Now it’s the same story, all over again. Genes -chunks of DNA that, ultimately, code for proteins- can be read in many ways and also modulated -favored, repressed- by other genomic sequences that do not code for proteins. And, there’s more. Genomic prose, as any decent piece of writing, follows an orthography capable of transmuting sense and meaning: epigenetics.
Now, this shouldn’t be news. The concept of epigenetics has been around for quite a long time. C. H. Waddington coined it in 1942, referring to the way in which genes might interact with the environment to produce a phenotype -an organism’s looks, if you will. But since he did so even before the formulation of DNA structure, let alone any knowledge of the genome, epigenetics needed a long gestation.
What we now know about it is fragmentary, tentative but definitely promising. There’s more than four bases to mammalian DNA. So far we know there are six of them, and the newcomers have been hidden beneath the veil of epigenetics. A Citosine chemically altered becomes mC -methyl citosine- and silenced at the same time. This mechanism has been known for a while but new developments revolutionized science las year. It was found that further alteration of mC resulted in hmC -hydroxy methyl citosine-, whose function remains unknown but is suspected to awake the base, somehow undoing the previous silencing.
Also, DNA is far from alone in the cell nucleus, it is intimately involved with proteins called histones that bend, fold and put order. These proteins can be altered, too, resulting in repression or activation of large portions of the genome.
From genes to features, from genotype to phenotype: paternal and maternal heredity -how the interaction between your father’s and mother’s contribution plays out-, chemical alteration of sequences and of proteins, too. No wonder why completing the Human Genome Project didn’t deliver the immediate, amazing, and revolutionary results a large portion of the public awaited. As with every other scientific discipline, the new century brought certain remains of mechanistic thinking -the rough or soft skin of Medel’s peas- to the complexity universe.
When sequencing the genome, complexity had to do with differences between individuals within a determined, although unknown, number of genes. Now, epigenomics is decidedly more complex. Sequence, protein or a combination of them can be marked in different ways, and we’re not talking a state here, but a dynamic process subtly modulated by a humongous set of variables.
Specific enzymes do the marking. These might be following a genetic program, such as the one guiding an undifferentiated zygote cell toward one of the photoreceptors catching light out of this screen and allowing your brain to make sense out the black and white pattern.
Diet can influence your epigenome: do you remember the 15 year old admonition of giving extra folate to pregnant women, so as to prevent nervous system’s defects to the baby? Well, folate is important and a lack thereof can severely damage the fetus or force abortion, but an excess’ been found to deregulate the epigenome in mice pups, producing behavioral abnormalities. It’s not just dietary supplements but virtually anything you feed your body has the potential to affect your epigenome: cigarettes, alcohol, abuse drugs, hormones, over-the-counter drugs…
Before going any further, a word of advice: instead of seeing pandemonium in the aforementioned sources of instability to your epigenome, think twice, it is not like we ever lived -or any other being, for that matter- in an environment that didn’t affect us. That’s the beauty of epigenetics, anything and everything demands a response, a balancing or counterbalancing effect from your part. Genes, as a fixed series of commands, were somewhat inelastic to do the deed. No more master plan to build your body and that’s that. In epigenetics we find the way for those genes to respond, to become ever more alive and active.
So, let’s recapitulate for a second. The Book of Life, our genome, is a long sequence of As, Gs, Ts, and Cs. To discern where a word starts and where another ends there’s alternative splicing and the few known words that mean “here starts something” or “here ends another thing”. On top of that, there’s long stretches of DNA that regulate what, when and how we get to read a passage, they’re called enhancers, promoters or regulatory sequences and those interact with enzymes and transcription factors which are created by the same DNA they regulate. A lot of feedback loops going on here, much like reading a sentence in English, though. Think of it: you know words, you follow syntax rules and you use context to resolve syntax conflicts. But this alone cannot untangle the long, interminable stretch of letters that build this Borgian Library of Babel. We need more accuracy, we need exquisitely fine discernment, to appreciate the subtleties composing that very Book of Life. That’s orthography rules and punctuation marks. That’s what epigenetics is all about.
Epigenetic modification allows you to draw parentheses before and after a sequence, thus silencing it without altering its content. You can put a metaphoric exclamation mark that increases its power and makes it more available to enzymes that mediate its expression. Maybe you put a sort of question mark, introducing the need for an answer, for another sequence producing an enzyme that erases it, allowing its normal expression. And then, there’s accents and silent letters, such as in many latin languages, where the same letters mean opposite or unrelated things depending on that extra sign over a vowel or that uncanny aphonic letter.
Of course, as any metaphor, I can only stretch it to a point before it collapses. There’s a significant slice of that subtlety that can only be found in the actual genome-epigenome system. So, with the general idea of what epigenetic regulation might be, let me sketch out a few cases illustrative of that system wrought havoc.
Action and re-action. The folate case illustrates how delicate a balance might be in place when it comes to epigenetics. Too few of it, and neural tube development gets impaired causing severe malformations or abortion. This case is interesting for folate comes from diet, and solar radiation breaks it while it circulates through our blood vessels. That is one of the factors possibly regulating human skin pigmentation -since the vitamin D hypotheses weakening due to Dr. Jablonski’s work. Folate is a molecule that lends a methyl group in many metabolic reactions, thus its vital importance. But its role and availability is what makes an excess of it end up imbalancing epigenetic systems and favoring too much methylation of citosines and histones. The result? Early embryo implantation in the maternal wound goes wrong.
Too little folate means birth defects and abortion, too much of it, too. This is a rather brief way to put it. Easy to store in memory for future occasions… or, is it?
There are two ways of memory, the immediate, short term memory that holds a phone number until you dial it, and the long term memory that stores pictures of your childhood until the end of life. This second type, the Long Term Memory, takes place in the hippocampus region of the human brain and, while it has a lot to do with physical networks made out of neurons, it also has a lot to do with epigenetics. For a connection to form, strengthen and ultimately live, changes have to take place. All changes, in this case, mean genes and products of genes doing their share of the work. Well, it now seems that methylation, or de-methylation, of histones in hippocampal neurons is key to the correct function of those genes responsible of long term memory formation.
So, watch your hippocampal histones if you want to remember! But, of course, memory can take many forms and epigenetics is the driving force behind one of the most uncanny among them. Imagine a relay race in which parents pass the baton to children… and grandchildren alike! In a cornerstone study in epigenetics, researchers looked for the faint memories in the genome of children gestated whilst the Duth Famine during the Nazi occupation of the Netherlands. They found them, in the form of a many-fold increase in risk of schizophrenia. But it could go as far as grandchildren, such as a british study that found grandfather nutrition’s effect on the pre-pubescent growth of their grandchildren.
Epigenetics can translate your decisions into undercover effects in your grandchildren’s life, a life that, lately, has experienced and increased risk of an unexpected turn. In the last 10 years there’s been a four-fold increase in diagnosis of Autism Spectrum Disorders. Following the first attempts to explain autism as a purely genetic disorder, scientist are finding more and more epigenetic clues. The preponderance of fatherly gene expression as opposed to motherly is behind some forms of autism. For long it’s been suspected that ASD were some sort of hyper-masculinization of the brain. Now differential imprinting of several genes is making up a short list of candidates for scientists to work on. Interestingly, since we’re looking at the many relation and complexity of epigenetics, some researchers say that not only ASD are the product of an all too male brain, but that they’re the natural opposite of Psychotic Spectrum Disorders, such as schizophrenia. Thus, making an extremely feminized brain the cause for several psychoses.
We could go on and on over the many ramifications of epigenetic research: cancer, pollutants, depression, obesity… but is another major branch of this complex universe I want to call your attention to.
Even though there’re tons of evidence piling on about methylation and gene regulation, there’s a number of unresolved issues. There’s a revolution going on in molecular biology, the High Throughput Sequencing revolution. The Human Genome Project costed $2.7 billion, ten years later we can have our genome sequenced for a few thousand dollars. Today, researchers can sequence DNA in search for methylations, and hydroximethylations, for a relatively low cost and a much, much better accuracy. But there’s no standards as to how to analyze the enormous quantities of data fruit of that research. It is not a matter of just making sense of the sequence, but that epigenetics is a very dynamic process for what we still don’t know enough: what is the neutral, balanced state of a gene? What are its interactions with other genes? If hmC is equals C that means methylation is a reversible process, but we still don’t know that!
Ten years after the Book was opened for the first time, we find ourselves more engaged than ever in deciphering its meaning, trying to grasp its syntax, to appraise every nuance of its prose. The work promises to be hard, and the rewards inmense.


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