At any given time, approximately 20% of the adult population is significantly impacted by pain, with most adults likely to experience pain at some stage during their lifetime. Chronic pain, including arthritis, back pain, diabetic neuropathy, shingles, cancers or injury, costs the Australian economy $140 billion annually. Current treatments options are limited, with ~70% of chronic pain patients not responding to available therapies.
Our inability to effectively treat pain arises from a poor mechanistic understating of pain’s onset, resolution or chronicity, including a limited identification of the proteins regulating these processes. One understood process, however, is that nerve pain is associated with extensive transcriptional changes that persist beyond injury resolution. This indicates an epigenetic mechanism of action. Given the inherent reversibility of epigenetic modification, identifying the enzymes responsible for these modifications and how their role is altered in different pain states, could provide a new approach to treating chronic pain.
We have identified a point mutation in the methyltransferase gene, SETDB2, in human patient who lack pain perception in response to thermal or mechanical stimuli. This role for SETDB2 is conserved from flies through to humans, underscoring its evolutionary importance. Mechanistically, we find that SETDB2 mutation sensitises primary sensory neurons to environmental stress and that SETDB2 interacts with cytoskeletal elements to regulate neurite outgrowth and neuronal connectivity. These findings provide new insights into pain perception and a potentially new avenue for chronic pain treatment in humans.