There are several ways in which this can happen. One is by the attachment of molecular “tags” to the respective genes, which might act as markers that deter the machinery of transcription, suppressing gene expression. Some genes can be switched off, for example, by proteins that stick a so-called methyl group – a carbon atom with three hydrogen atoms attached – onto DNA bases in the gene, which forms a sort of “shield” that protects the gene against being transcribed and translated into a protein. Another molecular mechanism of epigenetic regulation involves chemical changes to the histone proteins around which a stretch of DNA is wrapped in the chromosomes.
Harder to understand than this attachment of “leave me alone” labels to genes, but equally important for epigenetics, are processes that involve the packaging of DNA in chromosomes. Remember that the combination of DNA and histone proteins in chromosomes goes by the name of chromatin. This stuff is rather systematically coiled up and stowed when the chromosomes are in the compact form (typically X-shaped) found in dividing cells. At other points in the cell cycle, chromatin can be unwoven and loosely strewn, in which case the transcription machinery can get to it more easily. So how “active” genes are can depend on how the corresponding regions of the chromosomes are packaged.
An example of this epigenetic gene regulation happens in female cells, which contain two copies of the X chromosome, one passed on from each parent. If both of them were active, they would produce more proteins from this chromosome than the cell needs, and that would cause problems. So one X chromosome is inactivated early in the development of the embryo. The choice of whether to silence the maternal or paternal X chromosome is made by each cell at random and then passed on to daughter cells when they divide. The result is that females end up with an equal blend of two types of cell throughout their body. This process of X-chromosome inactivation was first identified by geneticist Mary Lyon in the 1960s. It took many years to figure out how “X-silencing” occurs, but we now know that it involves a gene that switches on a series of events resulting in the packaging of the inactive chromosome into a tight bundle, inaccessible to transcription. All the genes are still there and are faithfully copied and passed on when cells divide, but the shape of the chromosome keeps them hidden.
Some epigenetic changes to DNA that regulate gene activity happen automatically as cells divide and mature: each cell type will have its own characteristic pattern of epigenetic modifications. This too is why development of a fertilized egg into an embryo and then a mature organism isn’t exactly just a matter of reading out a genetic programme. It involves a continual, ever-changing process of epigenetic editing of that programme, taking place through time and space.
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In the mid-twentieth century, British embryologist Conrad Hal Waddington offered a metaphor for the process of epigenetic cell differentiation. He imagined cells in the early embryo traversing a landscape of possibilities: they begin their journey at a mountain peak and descend into valleys that branch like the channels of a river. At each branching point, the cell (more properly, the lineage of dividing cells) makes a decision about its subsequent fate: to become a progenitor of lung or heart, say. The consensus was that, once a lineage has descended into a valley, it can never reverse direction and go back uphill again.
The Waddington landscape. The balls represent the trajectories of different cell lineages, which begin in the single valley of totipotency as the zygote first begins to divide, and end in valleys representing different types of mature, differentiated cell.
Differentiation begins early. Indeed, it has happened even in the pluripotent embryonic stem cells of the epiblast, which have lost the totipotency of the earliest cells made from the dividing zygote. Already some of those first cells have been directed down the valley in Waddington’s landscape that leads to a placenta or a yolk sac, not to a part of the fetal body. The cells that make up the three layers of endoderm, mesoderm and ectoderm in the gastrulated embryo have undergone a further degree of differentiation, a further narrowing of choice.
It’s because of this specification of cell “fates” early in embryogenesis that the germ cells need to be formed so soon. Evidently a barely formed embryo doesn’t yet “need” eggs or sperm – but it must put aside the cells from which they will grow before they lose too much of their pluripotency. The germ cells, after all, have to make a totipotent zygote, so it won’t do if their chromosomes have already been heavily modified and silenced. Germ cells do have some epigenetic silencing of genes, although this too must be stripped away when the gametes combine to make a totipotent zygote.
This special dispensation for germ cells aside, epigenetic changes appear to be one-way. They partly account for how our body tissues remember and maintain their identity as they grow: why skin cells divide to produce more skin cells, and don’t spontaneously become muscle cells or stem cells. In other words, cell replication is somewhat more complex than merely a matter of copying the chromosomes. It’s necessary also to copy the epigenetic chromosomal modifications that give the cell its identity.
What this means is that each cell in our bodies, like each one of us, has a lineage: an ancestral history that starts with the zygote – and, except for a handful of germ cells (if we have children), ends in the grave. A liver cell has arisen from an embryonic stem cell via a succession of ancestors with intermediate characteristics, reflecting an ever greater specialization and loss of versatility. This notion of cell lineages was first articulated clearly by August Weismann when he drew up his fundamental distinction between somatic (“mortal”) and germ (“immortal”) cells.
When we tell the story this way, a new possibility becomes apparent. In cells during development, just as in organisms during evolution, genes can change. Every time a cell divides, there is a chance that some of the three billion base pairs in the genome will be miscopied – that the daughter cells will acquire mutations. Cells put a great deal of effort into avoiding such mistakes, employing a kind of molecular proofreading to check for errors in replication. All the same, the numbers are so vast that mutations are inevitable. It’s estimated that distributed within the chromosomes of our 37 trillion or so cells are about ten thousand trillion genomic mutations.13 Every one of our genes experiences somatic mutations at some point in our lives.
Most of these mutations, fortunately, don’t matter – they don’t affect a gene’s ability to do its job(s). But some have consequences. Most notoriously, gene mutations can lead to the cell dysfunctions that cause cancer (see here). Even potentially harmful mutations, though, might not matter if they happen late in development and so appear only in a few cells. Somatic mutations that arise during early embryo growth, on the other hand, may be passed on to all subsequent cells in that lineage, making the developing body a patchwork or “mosaic” with slightly but perhaps significantly different genomes. There are many diseases related to “mosaicism”, of which cancer is just one class. Somatic mutations leading to mosaicism are particularly common in brain neurons, and they are thought to be responsible for a range of brain and cognitive disorders, including some types of autism. Even benign mutations can manifest themselves in outward appearance (that is, phenotypically): for example, causing striped skin pigmentation called Blaschko’s lines or the red skin blotches called port-wine stains.
One particularly unusual but very rare kind of mosaicism happens when a cell in a male embryo fails to pass on its Y chromosome to the daughter cells, which, inheriting only the X, then develop as “female cells” by default. This can lead to a mixture of male and female characteristics in the embryo. Rare it may be, but this condition serves to remind us of the cell’s autonomy. Even in a body “meant” (to judge from the zygote) to be male, there is no global command that cells obey, and the “feminized” cells will feel no obligation to conform to the nature of their “male” neighbours.
Genetic
