An unexpected neuro-osteo genomic link
Diagram from NatureComms Article showing the different techniques and epigenetic markers used in the experiments as DNA structure is whittled down.
READING TIME: 8 minutes
NatureCommunications recently reported a study that showed the unanticipated genomic link between Huntington’s disease and rheumatoid arthritis (RA). Huntington’s disease is an inherited disorder which is classified as a neurodegenerative disease: it leaves the individual with chorea, physical instability and impaired psychomotor control. RA is an autoimmune disease which results in the complication of joint pain, as well as heart and lung inflammation in some individuals. This joint pain is thought to be the result of genetic and epigenetic factors (processes that change gene expression without changing DNA itself); these processes are environmentally influenced by changes in lifestyle and activity.
The overlap was discovered when researchers at the University of California San Diego School of Medicine and the Icahn School of Medicine at Mount Sinai were working on finding epigenetic markers for RA. The team used a programme called EpiSig, which is an unbiased method, using an algorithm that documents epigenetic combinations amongst a wide variety of patient data associated with RA. They compared 125 clusters between 11 patients with rheumatoid arthritis and 11 patients with osteoarthritis (OA) (the control group) and the team studied chromatin, DNA and histone modifications - these are all targets that expose our genes to epigenetic change meaning they all contribute to certain genes between switched on or off.
By using multiple technologies such as WGBS, ATAC-seq and RNA-seq they documented the subtle epigenetic expression of fibroblast-like synoviocytes (FLS) which are cells that lie in the synovium of joints that contribute to the aggressive phenotype in inflammatory arthritis. 13 enriched clusters included regions which highlighted histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, H3K9me3), open chromatin, RNA expression, and whole-genome DNA methylation. They also stumbled upon discovering that Huntington-interacting protein 1 (HIP1) regulates FLS invasion into the matrix showing that Huntington Disease cell signalling has relevant cell signalling patterns in RA. The specific role in the immune-response is still unknown but by depleting HIP1 in RA cells, FLS invasion decreased by almost half, suggesting an association between HIP1 and FLS cells. This pathway was the most commonly enriched pathway which came as a shock due to the lack of association of Huntington’s disease with immune-mediated diseases. Being able to validate this key protein in Huntington Disease Signalling using this new unbiased method means other potential therapeutic targets could be discovered too.
Treatments for both diseases only temporarily alleviate symptom discomfort and some patients do not even respond to medicines. Personally when I was working on a laboratory project looking at the contribution of glucocorticoid metabolism and the characterisation of bone loss in inflammatory arthritis there was no discussion of association between the two diseases. Therefore by establishing the first high-resolution global epigenomic landscape for RA and connections between the unlikely but similar genetic markers between the two diseases, this could introduce new projects and new viewpoints to study associations and drug targets and even repurpose existing drugs in these diseases. The new technology used to discover this phenomenon could also prove useful in finding potential links between other disease states which are not commonly associated as being similar to each other which could also open up new research fields.
REFERENCES
