Tuesday, November 24, 2015

Epigenetics: what is it and what isn't it? Part I: basic ideas

Epigenetics is a word that has had a variety of meanings historically, and it's sometimes unclearly employed, even by the user.  But these days, when people talk about epigenetics they generally mean the chemical modification of DNA sequence in a way that does not change the sequence itself but affects the expression of genes in or near the modified DNA region--that is why it is called 'epi' genetic. Such chemical modifications affect whether or not the cell uses a particular gene (only a subset of all genes is used in any particular cell, but that subset changes depending on the cell's local environment at any given time). That is, epigenetic changes essentially are regulatory; the epigenetically modified DNA sequences are not mutations of the coding of the structure of a particular protein (or a directly functional RNA), just how or when or how intensely it is used by the cell. Likewise, epigenetic modification doesn't change the affected sequence itself, but affects whether regulatory proteins can bind there to cause a nearby gene to be expressed, that is, transcribed into RNA.  The phenomenon of such DNA 'marking' itself isn't controversial, and a few of the means by which it happens in a cell are known.  Indeed, unlike mutations in the sequence itself, the marking is easily erased and there are known mechanisms that do that.

However, reports that epigenetic marking can be inherited are quite legitimately controversial.  There are a few reasons for this.

How can local gene usage be inherited?

Cells respond to their environment--to extra-cellular conditions--via cell-surface receptors or other similar means.  If they don't have receptors for a signal floating by, they can't detect or respond to that signal. But cells that do detect a signal change whether they start or stop using a particular set of genes. That's how complex multicellular, multi-organ system organisms become differentiated, as well as to respond to environmental conditions.  Most examples of epigenetic inheritance relate to experience that affects particular types of cells, though many 'housekeeping' genes, genes that carry on basic metabolism, are used by all cells, and any environmental change could in principle induce all cells to change their gene usage.

Unless there is subsequent environmentally-induced change, once modified, when they divide, cells transmit their particular expression state to their daughter cells. 
If an epigenetic modification causes a cell to respond to a particular environmental signal by turning on the expression of a particular gene, that 'use it!' state would be passed on when the cell divides to produce other cells in its lineage, unless or until another modification occurred to reverse the original change. Thus, if some particular cell, say a lung cell, is induced by some environmental factor like a nutrient to express some set of lung-related genes, the effect is local, specific to lung cells. How that works is complex but some of the mechanisms are known.  However, they have to do with how chromosomes specifically in lung cells are packaged; that is a local fact.  For example, it need not also affect nerve or vessel or skin or stomach cells.  Again, that is because in a differentiated organism different tissues are separated from each other so they can be different.

This raises a serious problem: Local effects on gene expression will be passed on to daughter cells in that tissue, but this is not the same as transmitting the effect to the next generation of organisms. Intergenerational transmission requires that the modification also be made in germline--sperm or egg cells--because the offspring organism starts out life just as a single fertilized egg (which has no lung cells!). Germline cells generally need to have genes switched on (or off) to enable them to make a new organism from scratch, from that single fertilized egg cell. Some temporary change that was important to the embryo's future lung cells would not likely be appropriate for the development of those cells in the first place during embryogenesis. So it is no surprise that there are active mechanisms to strip off epigenetic changes in germ cells' DNA, to reprogram those cells' gene usage to prepare them for their embryonic duties, this is done by erasing and re-setting DNA modification in the sperm or egg cell. If the embryo's lungs, when they eventually have them, need to modify what they due based on the air their exposed to, then new epigenetic changes will occur. Thus, the process of erasing and reprogramming removes those changes. Some bits of the genome are protected from this but it is not automatically true that even environmentally induced changes in housekeeping gene usage will be transmitted.

It was first systematically shown by Weismann in the 19th century and has been a theoretical bulwark against the idea of Lamarckian inheritance, that at least in most animals, somatic (body) and germline cells are separated, independent lineages isolated from each other (the situation is different in many or most plants).  That means that for epigenetic changes to become heritable--and hence affect evolution--modifications to particular body cells would have to be applied to germline cells and not be erased before fertilization.

Without some clear mechanism, there is no reason that future sperm or egg cells will even 'know' about, much less respond to, the signal that induces change in the lung or nerve or stomach cells.  So for epigenetic change to be inherited, there is the serious question of how the genomes in germline cells are specifically modified by signals that affect nerve or lung, etc.  If a lung cell alters its use of gene X related to how lungs work, when it detects some (say) pollutant in the air, how does that specific change also get imposed on the germ line?  Explanations that have been suggested so far are mainly not very convincing. That's why most reports of inherited epigenetic modification are properly received with skepticism.

Still, many investigators are seriously interested in epigenetic changes, especially when or if they are inherited, for a few reasons. This sort of inheritance, which modifies DNA usage differently among a person's many different localized tissues, threatens the degree to which traits can be predicted from a person's DNA sequence alone (obtained, for example, from a blood sample), and among other things that threatens realization of the promise of 'precision' genome-based medicine.  Secondly, accurate assessment of epigenetic effects could lead to a better understanding of important environmental exposures and/or what to do about them, so that newborns are not doomed by their parents' habits to live with pre-set epigenetic traits that they now cannot prevent.  And the least legitimate reason, but one important in the real world of today is that is a lucrative and sexy new finding that can be made to seem a melodramatic 'transformative' shift in our understanding of life.

An important criterion for claims of true epigenetic inheritance is that they must pass through at least to a 3d generation without the presence of the environmentally causal trigger.  That is, transgenerational transmission is evidence that the genome is in fact preserving the change rather than just each new individual learning it from environmental experience (such as in utero).  While there have been various generally convincing reports of true transgenerational inheritance in some species like the simple nematode (C. elegans) or plants, this hasn't clearly been shown in mammals (or humans), even if one or even two generational inheritance, usually through the maternal line, has been found.

Most of the literature consists of curious reports or claims of epigenetic inheritance, reviews of the germline erasure process and what areas of germline DNA could perhaps escape erasure of epigenetic marking, and some examples that seem to be truly transgenerational.  At present, the excitement seems generally far exceeding the reality.  But since epigenetics is potentially quite important, and the methods for understanding it rather new, it is being given serious attention.

A paper by Bohacek and Mansuy (November 2015 Nature Reviews Genetics), reviews what is known about the degree to which epigenetic 'marking' is inherited.  This is a very good, measured paper that in our reading of it makes it clear that claims of non-trivial multi-generational DNA modification effects still need careful documentation.  But if life-experience by parents can affect their offsprings' traits in substantial ways related to the offsprings' future life experience, even if they are not exposed to the risk factors that set their parents' genome usage patterns, then if we could understand how this works perhaps such modifications would not be destiny, and means of prevention or control could be developed if the phenomenon were to be better understood.

Gene usage isn't the same thing as gene structure
Epigenetic inheritance can also affect ideas about how evolution works, if they really have long-term (many generational) effects. The suggestion is now routinely being made that the phenotypic effects of epigenetics we are seeing introduces a Lamarckian view of evolution that may, after all, have to be melded with our Darwinian theory (e.g., see Skinner, MK, Gen Biol Evol. 7: 1296-1302, 2015).  But the idea that this is a genuine revival of Lamarckism is still treated with sneering.  Should it be?

We have written a 2015 series of posts about Lamarckian ideas.  Lamarck was interested in the evolution of adaptive traits, like flying or ocean-living mammals, not just some specific minor traits. He had some non-starter ideas, but so did Darwin and they had far less knowledge than we do!  So one can't defend his theory per se for various reasons.  Still, it's worth thinking about rather than just sneering at Lamarck.  That's for tomorrow's post.....

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