At a conference in Cambridge in 2010, the same authors reported that one of the major environmental changes in Iceland from 1820 to the present day was a shift from a traditional diet to more mainstream European fare[302]. The traditional Icelandic diet contained exceptionally high quantities of dried fish and fermented butter. The latter is very high in butyric acid, the weak histone deacetylase inhibitor. Histone deacetylase inhibitors can alter the function of muscle fibres in blood vessels[303], which is relevant to the type of stroke that patients with this mutation suffer. There is no formal proof yet that it’s the drop in consumption of dietary histone deacetylase inhibitors that has led to the earlier deaths in this patient group, but it’s a fascinating hypothesis.
The fundamental science of epigenetics is the area that is most difficult to make predictions about. One fairly safe bet is that epigenetic mechanisms will continue to crop up in unexpected parts of science. A good recent example of this is in the field of circadian rhythms, the natural 24-hour cycle of physiology and biochemistry found in most living species. A histone acetyltransferase has been shown to be the key protein involved in setting this rhythm[304], and the rhythm is adjusted by at least one other epigenetic enzyme[305].
We are also likely to find that some epigenetic enzymes influence cells in many different ways. That’s because quite a few of these enzymes don’t just modify chromatin. They can also modify other proteins in the cell, so may act on lots of different pathways at once. In fact, it has been proposed that some of the histone modifying genes actually evolved before cells contained histones[306]. This would suggest that these enzymes originally had other functions, and have been press-ganged by evolution into becoming controllers of gene expression. It wouldn’t therefore be surprising to find that some of the enzymes have dual functions in our cells.
Some of the most fundamental issues around the molecular machinery of epigenetics remain very mysterious. Our knowledge of how specific modifications are established at selected positions in the genome is really sketchy. We are starting to see a role for non-coding RNAs in this process, but there are still multiple gaps in our understanding. Similarly we have almost no idea of how histone modifications are transmitted from mother cell to daughter cell. We’re pretty sure this happens, as it is part of the molecular memory of cells that allows them to maintain cell fate, but we don’t know how. When DNA is replicated, the histone proteins get pushed to one side. The new copy of the DNA may end up with relatively few of the modified histones. Instead, it may be coated with virgin histones with hardly any modifications. This is corrected very quickly, but we have almost no understanding of how this happens, even though it is one of the most fundamental issues in the whole field of epigenetics.
It’s possible that we won’t be able to solve this mystery until we have the technology and imagination to stop thinking in two dimensions and move to a three-dimensional world. We have become very used to thinking of the genome in linear terms, as strings of bases that are just read in a straightforward fashion. Yet the reality is that different regions of the genome bend and fold, reaching out to each other to create new combinations and regulatory sub-groups. We think of our genetic material as a normal script, but it’s more like the fold-in from the back of Mad magazine, where folding an image in a particular way created a new picture. Understanding this process may be critical for truly unravelling how epigenetic modifications and gene combinations work together to create the miracle of the worm or the oak or the crocodile.
Or us.
So here’s the summary of what epigenetic research will hold in the next decade. There will be hope and hype, over-promising, blind alleys, wrong turns and occasionally even some discredited research. Science is a human endeavour and sometimes it goes wrong. But at the end of the next ten years we will understand more of the answers to some of biology’s most important questions. Right now we really can’t predict what those answers might be, and in some cases we’re not even sure of the questions, but one thing is for sure.
The epigenetics revolution is underway.
Glossary
Autosomes The chromosomes which are not sex chromosomes. There are 22 pairs of autosomes in humans.
Blastocyst Very early mammalian embryo, consisting of about 100 cells. The blastocyst comprises a hollow ball of cells that will give rise to the placenta, surrounding a smaller, denser ball of cells that will give rise to the body of the embryo .
Chromatin DNA in combination with its associated proteins, especially histone proteins.
Concordance The degree to which two genetically identical individuals are identical phenotypically.
CpG A cytosine nucleotide followed by a guanine nucleotide in DNA. CpG motifs can undergo methylation on the C.
Discordance The degree to which two genetically identical individuals are non-identical phenotypically.
DNA replication Copying DNA to create new DNA molecules which are identical to the original.
DNMT DNA methyltransferase. An enzyme that can add methyl groups to cytosine bases in DNA.
Epigenome All the epigenetic modifications on the DNA genome and its associated histone proteins.
ES Cells Embryonic stem cells. Pluripotent cells experimentally derived from the Inner Cell Mass.
Exon Region of a gene that codes for a section that is present in the final version of the mRNA copied from that gene. Most, but not all, exons encode amino acids in the final protein produced from a gene.
Gamete An egg or a sperm.
Genome All the DNA in the nucleus of a cell.
Germline The cells that pass on genetic information from parent to child. These are the eggs and the sperm (and their precursors).
HDAC Histone deacetylase. An enzyme that can remove acetyl groups from histone proteins.
Histones Globular proteins that are closely associated with DNA, and which can be epigenetically modified.
Imprinting Phenomenon in which expression of certain genes depends on whether they were inherited from the mother or the father.
Inner Cell Mass (ICM) The pluripotent cells in the inside of the early blastocyst that will give rise to all the cells of the body.
Intron Region of a gene that codes for a section that is removed from the final version of the mRNA copied from that gene.
iPS Cells Induced pluripotent stem cells. Produced by reprogramming mature cells with specific genes that cause terminally differentiated cells to revert into pluripotent ones.
kb Kilobase. 1,000 base pairs.
miRNA Micro RNA. Small RNA molecules that are copied from DNA but that don’t code for proteins. miRNAs are a subset of ncRNAs
mRNA Messenger RNA. Copied from DNA and codes for proteins.
ncRNA Non-coding RNA. Copied from DNA and doesn’t code for proteins.
302
Abstract from Palsdottir et al. (2010),