Latent enhancers - a novel mechanism for pain chronification?

All of us are likely to know someone that suffers from chronic pain - it is a very common condition, which can be caused by sports injuries, various diseases and the process of ageing. Treatment options are limited, and doctors are often unable to offer anything more than partial relief with a prescription of painkillers, leaving their patients resigned to suffering.

While chronic pain can have many different causes, the outcome is often the same: an overly sensitive nervous system which responds much more than it normally would. However, a question still remains as to why the nervous system should remain in this sensitive state over long periods of time, especially in instances where the underlying injury or disease has gone.

This grant seeks to investigate this paradox. It is based on findings that nerve damage can change epigenetic marks on some of the genes in immune cells that are known to be important for the generation of persistent pain. Epigenetics is the process that determines which gene is expressed and where. Some epigenetic signals have direct functional consequences, while others are just primers: flags that indicate a potential to act or be modified.

This grant is designed to investigate this phenomenon further: we would like to find out whether a chronic pain state alters epigenetic marks not only in immune cells, but also in neurons, and we would like to investigate the functional consequences of these alterations. Our overall hypothesis is that the many small injuries we encounter over our lifetimes - innocuous in isolation - might leave a plethora of molecular 'footprints', which can add up to more lasting damage, and ultimately chronic pain.

This project is concerned with the question of why painful conditions should persist over many years, despite the fact that the initial injury or disease has remitted. It is a phenomenon commonly observed in the clinic, where patients might for instance be plagued by back pain long after the initial sports injury healed. What is known is that their nervous system appears to have adopted a permanent maladaptive state as a result of an initial condition. What is unknown is what molecular mechanisms enable this maladaptive state to persist over long periods of time. This project investigates the novel hypothesis that the emergence of latent enhancers permanently alters the phenotype of the neurons and immune cells involved in nociception - ultimately turning acute pain into a lasting chronic condition.

Latent enhancers are regulatory regions that emerge in the genome as a result of stimulation once cell development is complete. They have been shown to occur in immune cells, and I have recently been able to observe their appearance in mouse microglia in a model of chronic pain (Denk et al, Cell Reports, 2016). Based on this work, this proposal aims to answer the following three questions:
1. Do latent enhancers also emerge in neurons, where nociception ultimately takes place?
2. Do latent enhancers display characteristics that would allow them to act as a molecular memory?
3. Does the deposition of latent enhancers have functional consequences?

Enhancer profiles ultimately determine cell identity, and post-developmental changes to these profiles could therefore affect cell function in the long term. The results of this work would help elucidate the origins of chronic pain, ultimately facilitating the search for effective prevention or treatment. They would also help uncover generic mechanisms of how the environment can impact gene function in a cell-type specific manner.

As discussed in the 'Academic Beneficiaries' section, I think it likely that the proposed research will have important and wide-reaching academic impact if it were to be funded. Beyond that, a deeper understanding of how chronic pain develops could have far-reaching economic and societal impact.

Knowledge of whether and how enhancer deposition might impact chronic pain conditions could inform drug development by opening up the possibility of treatment with compounds hitting epigenetic targets. Moreover, deeper understanding of this mechanism might open up avenues to explore preventative and/or targeted treatments. This could have direct positive economic impact for the pharmaceutical industry as well as for charities and funding bodies examining future research proposals.

Better understanding of chronic pain will also benefit health practitioners and patients and ultimately the general public. This is true whether or not new drugs would result from this research, since new information can often lead to positive change for doctors and patients even without the advent of new medication. For instance, chronic pain has historically often been dismissed as a "psychological problem". Research has helped revise and refine this view, and it is now believed that while mood and stress can clearly influence pain perception, there almost always is also a clear underlying physiological cause. This can be of great comfort to patients and their families, and help on the road to recovery.

I hope that epigenetic research might also shed light on how "useful" and necessary acute pain states get transformed into maladaptive chronic pain. This could be of great relevance to the general public, as it might lead to guidelines on whether there are certain things one may be able to do to avoid developing chronic pain. The potential impact on health practitioners, patients and the general public could be both societal, increasing general quality of life by reducing pain, as well as economic. Reducing the incidence and/or the duration of chronic maladaptive pain in the population could save the government and individuals large sums of money that are being incurred through sick leave, poor efficiency at work as well as treatment costs.