Mind the gap: it's not as robust as you thought…

The gap is the one between genome and phenotype, which we will struggle to understand for some time, despite, or perhaps because of, the rapidly advancing field of epigenetics. A ‘message’ communicated by systems biology is that (counter to previous thinking) biological systems are generally highly robust – a necessity for gene networks underlying embryonic development and adult homeostasis. And one of the ‘messages’ emerging from RNA epigenetics is that microRNAs are probably the fine-tuners of network properties, rather than the grand orchestrators. However, in certain respects, those messages might well be wrong, or at least have crucial exceptions. An interestingmessage on the power of epigenetics (broad meaning) was sent by the recent twin study of Baranzini et al. [1], which demonstrated no detectable difference at the level of genome sequence, epigenetic marks or gene expression levels (mRNA) in CD4þ lymphocytes of monozygotic twins, one of which has multiple sclerosis, the other of which is free of the disease. Might non-coding RNAs (ncRNAs), even transiently expressed or overexpressed, be the key? Findings thatmicroRNAs are responsible for some pivotal and large changes in development and function of immune cells (for a review see Ref. [2]) are revising the notion that they are merely fine-tuners. Those gene expression networks are certainly not robust to several-fold increases in microRNA concentration. As presented in this issue, ncRNAs are emerging as major constituents of the non-coding genome, many of them important regulators (Fabricio Costa [3]), and, together with RNA editing, they might embody the very substrate of epigenome-environment interactions (John Mattick [4]). We know very little about how environmental stimuli modulate gene expression networks – via signal transduction pathways, for instance. I will hazard a speculation that epigenetic stimuli acting through such pathways can have very large effects because of the cascade nature of the pathway, and the signal amplification at various points. That is what one would expect if a stimulus is a normal part of the response of the immune system, which must make a pivotal change in response to a short-lived ‘‘spike’’ of external ligand. Should a transient environmental stimulus activate such a powerful modulator of gene expression in the wrong cell, at the wrong time, it might not leave a signature in the sense of epigenetic marks or mRNA levels; rather it might permanently change the stable equilibrium of the system at a higher level, e.g. cell or tissue – an example of a ‘high level’ emergent property that is not ‘coded’ in the architecture of lower levels. Even if the networks at different hierarchies are largely robust, the combination of their small, or large but transient, fluctuations could reorient the higher order system in the longer term. The usefulness of Waddington’s concepts of epigenetics is noted in two articles in this issue for explaining evolutionary genetics via systems biology (Jonathan Bard [5]), and the generation and modulation of phenotypic variation (Heather Jamniczky et al.[6]); by extension, Waddington’s epigenetic landscapes could be applied systematically to investigate environmental stimuli that cause disease: imagine distorting different levels of network landscapes (e.g. gene expression, whole-cell physiology, tissue function/architecture) in silico, to ascertain the new equilibria. If those mimic the disease state, or its trigger, the point(s) of initial distortion could be indicators to the more remote site of action of the environmental stimulus: ‘environmentally vulnerable’ components in networks might, thus, be identified, possibly suggesting which kinds of environmental, or medical, stimuli could reverse the disease state. The analogy that we are, upon conception, dealt a ‘poker hand’, the strength of which unfolds ‘randomly’ as other (environmental) players in the great game of life lay down their cards, is partially tenable (with the exception of mono-genetic diseases, for example). But progress can probably be made through an appreciation of the potentially strong effects of epigenetic factors, development of Waddington’s principles in the light of systems biology and the concept of the emergence of function and dysfunction as a result of the superposition of layers of hierarchical organisation. Thenwemight be able to glimpse our opponents’ hands, or even replay a move in the game.