The Epigenetics Revolution

But if ncRNAs are so important for cellular function, surely we would expect to find that sometimes diseases are caused by problems with them. Shouldn’t there be lots of examples where defects in production or expression of ncRNAs lead to clinical disorders, aside from the imprinting or X inactivation conditions? Well, yes and no. Because these ncRNAs are predominantly regulatory molecules, acting in networks that are rich in compensatory mechanisms, defects may only have relatively subtle impacts. The problem this creates experimentally is that most genetic screens are good at detecting the major phenotypes caused by mutations in proteins, but may not be so useful for more subtle effects.

There is a small ncRNA called BC1 which is expressed in specific neurons in mice. When researchers at the University of Munster in Germany deleted this ncRNA, the mice seemed fine. But then the scientists moved the mutant animals from the very controlled laboratory setting into a more natural environment. Under these conditions, it became clear that the mutants were not the same as normal mice. They were reluctant to explore their surroundings and were anxious[158]. If they had simply been left in their cages, we would never have appreciated that loss of the BC1 ncRNA actually had a quite pronounced effect on behaviour. A clear case of what we see being dependent on how we look.

The impact of ncRNAs in clinical conditions is starting to come into focus, at least for a few examples. There is a breed of sheep called a Texel, and the kindest description would be that it’s chunky. The Texel is well known for having a lot of muscle, which is a good thing in an animal that’s being bred to be eaten. The muscularity of the breed has been shown to be at least partially due to a change in a miRNA binding site in the 3′ UTR of a specific gene. The protein coded for by this gene is called myostatin, and it normally slows down muscle growth[159]. The impact of the single base change is summarised in Figure 10.4. The final size of the Texel sheep has been exaggerated for clarity.

^{Figure 10.4 A single base change which is in a part of the myostatin gene that does not code for protein nevertheless has a dramatic impact on the phenotype in the Texel sheep breed. The presence of an A base instead of a G in the myostatin mRNA leads to binding of two specific miRNAs. This alters myostatin expression, resulting in sheep with very pronounced muscle growth.}

Tourette’s syndrome is a neurodevelopmental disorder where the patient frequently suffers from involuntary convulsive movements (tics) which in some cases are associated with involuntary swearing. Two unrelated individuals with this disorder were shown to have the same single base change in the 3′ UTR of a gene called SLITRK1[160]. SLITRK1 appears to be required for neuronal development. The base change in the Tourette’s patients introduced a binding site for a short ncRNA called miR-189. This suggests that SLITRK1 expression may be abnormally down-regulated via such binding, at critical points in development. This alteration is only present in a few cases of Tourette’s but raises the tantalising suggestion that mis-regulation of miRNA binding sites in other neuronal genes may be involved in other patients.

Earlier in this chapter we encountered the theory that ncRNAs may have been vitally important for the development of increased brain complexity and sophistication in humans. If that is the case, we might predict that the brain would be particularly susceptible to defects in ncRNA activity and function. Indeed, the Tourette’s cases in the previous paragraph give an intriguing glimpse of such a scenario.