After the recently published Lamarck’s Revenge: How Epigenetics Is Revolutionizing Our Understanding of Evolution’s Past and Present left me little the wiser on how epigenetics actually works, I decided to track down a copy of Nessa Carey’s The Epigenetics Revolution. As one of two popular books published around the same time, it seemed like a good place to start. Peter Ward was right about one thing, this is indeed a landmark book, even if it is now a few years old.
Just to make sure everyone is on the same page, a quick definition: epigenetics is the study of changes in an organism caused by changes in gene expression rather than in the genetic code itself. So, up- or down-regulation of gene activity rather than mutation. Carey starts off with a history of the first researchers that asked the right kinds of questions that led to the discovery of this field. After all, if every cell in a human (or animal) body contains all the DNA, all the genetic instructions to make a complete version of itself, then why doesn’t it? How do cells actually become so specialised to be skin cells, liver cells, or muscle cells? Do they just jettison all the genes they don’t need anymore? Or do they retain them but switch them off?
This is where epigenetics comes in. Carey introduces the various molecular mechanisms, including DNA methylation: the addition of a methyl group, or –CH3 if you remember your chemistry classes, to DNA; and histone modification: changes to the structural protein around which DNA coils to form a larger superstructure. Her clear explanations and the many drawings included immediately answered some burning questions I had after reading Lamarck’s Revenge. DNA methylation is supposed to be quite stable, but how is it passed on during cell division when all that is duplicated is the DNA? It turns out that once you look at the biochemical details, DNA replication is a tad more complicated than that. There is a class of proteins called DNA methyltransferases dedicated to recreating methylation markers on a strand of freshly synthesized DNA.
Carey also talks about monozygotic or identical twins. In his recent book, Plomin surveyed the long-term twin studies he has been involved in (see my review of Blueprint: How DNA Makes Us Who We Are). One of his (paraphrased) take-home messages was: “Look at how identical these twins are, and how powerful a tool this has been to show that genetics is a huge determinant of behaviour.” And this is true. Yet, despite being 100% genetically identical, such twins are not *completely* identical, and differences accrue as twins age. Epigenetics offers an answer, with differences in environments experienced – starting in the uterus – leading to different epigenetic profiles or epigenomes.
“if every cell in a […] body contains all the DNA, all the genetic instructions to make a complete version of itself, then why doesn’t it?”
In subsequent chapters, Carey walks the reader through the many wonderful findings that have emerged from this field. How life experiences, such as a famine, that caused epigenetic changes can resonate down the generations and affect children and grandchildren. How epigenetic markings are wiped almost, but not quite, completely so that a sperm or egg cell, which is very specialised, can again become a completely undifferentiated cell capable of forming all the cells making up the human body. How a cell knows which chromosome came from the father, and which from the mother (and why that matters). How it can offer a mechanism explaining why traumatic childhood events leave a lasting legacy, whether physical or mental. And how understanding epigenetics can offer us a new way to understand and possibly combat diseases such as cancer.
One topic is worth highlighting in particular, as it is the subject of her second book Junk DNA: A Journey Through the Dark Matter of the Genome published three years later. We know that humans have a comparable number of genes to, say, the small soil nematode Caenorhabditis elegans, a particularly popular model organism in biological research. But what sets us apart is the amount of DNA that we have that does not code for proteins: some 98% versus 75% for C. elegans. That’s a huge difference! For every base pair in human DNA that codes for a protein, we have 49 that do not code for a protein, whereas that little worm only has three. Initially, this genetic “dark matter” was called junk DNA, but a large portion of it is actually useful, no, vital even.
“the multi-layered networks of gene regulation are a bit like that game Mousetrap: cobbled together from repurposed, multifunctional parts, and ludicrously complex”
From my review of Gene Machine: The Race to Decipher the Secrets of the Ribosome you will remember the basics of the story. DNA is read and transcribed into a single-stranded form of nucleic acid called RNA. This is then transported out of the cell nucleus to the ribosome that resides in the cytoplasm (the area of a cell outside of its core). The ribosome then translates the RNA into proteins which do all the actual work in living cells. But only 2% of DNA in humans codes for this. It turns out that in the other 98% there is also a huge amount of activity and DNA is constantly being transcribed into RNA. But this RNA never leaves the cell nucleus. It isn’t even turned into proteins! This non-coding RNA (bit of a misnomer as Carey points out) is biologically active though and is another epigenetic marker. Long stretches of non-coding RNA can latch on to DNA and suppress or stimulate gene expression. Shorter stretches can bind to the messenger RNA that is ferried from the cell nucleus to ribosomes, which offers yet another avenue for up- or down-regulation of gene expression. This is fascinating stuff that was new to me and really makes me look forward to reading Junk DNA (which I already have on order).
Early on, Carey mentions that the multi-layered networks of gene regulation are a bit like that game Mousetrap (or Rube Goldberg machines for an older generation of readers): cobbled together from repurposed, multifunctional parts, and ludicrously complex. Carey follows a clear approach in each chapter of discussing the key studies that led to certain major insights. She goes into a fair level of detail, and I wouldn’t be surprised if your eyes glaze over a bit at the alphabet soup of gene names and the details the winding, Mousetrap-esque signalling cascades. But she is quick to focus on the big picture of these experiments and provides many helpful illustrations that offer a graphical summary of the main points.
Written with much love for the field, and laced with a sense of humour and many amusing but useful analogies, Carey shows herself to be a gifted writer that can make this field accessible for readers new to the topic, while providing a level of depth and detail to satisfy an audience of fellow biologists. I have not yet read Francis’s book Epigenetics: How Environment Shapes Our Genes, published around the same time, but The Epigenetics Revolution is a superb introduction to the topic that answered many of my basic questions. The fact that it remains a useful introduction in such a fast-moving field is a huge achievement.
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