#apaperaday: The discovery of the DNA methylation episignature for Duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: The discovery of the DNA methylation episignature for Duchenne muscular dystrophy

Today’s pick is by Schreyer et al from the World Muscle Society journal neuromuscular disorders on methylation profiles of blood cells in Duchenne patients. DOI: 10.1016/j.nmd.2022.12.003

I thought I caught the authors at a wrong assumption but it turned out not to be the case. Here we go: Duchenne is characterized by loss of dystrophin, progressive muscle weakness and loss of function.

Still there is variability between patients with regards to when they experience disease milestones and how they respond to treatments like corticosteroids. Genetic modifiers have been discovered that explain part of the variability but there has to be more.

DNA can be modified by cells to increase or decrease expression of each gene. This is called epigenetics. Differences in epigenetics can underlie differences in disease progression. Eg if inflammatory genes are depressed progression will be slower than when these genes are active.

Authors here study epigenetic profiles of blood cells of 36 Duchenne patients and 72 age and sex matched controls. 33 patients were using steroids. 31 Duchenne epigenetic profiles were clearly distinct from the controls while 5 were not. Authors dove into these 5 and this group contained the 3 non steroid users and 2 patients known to have poor compliance with steroid use. So – I thought- the epigenetic profiles are not Duchenne specific but rather steroid specific. Fortunately the authors also thought this.

They did an extra comparison: comparing the Duchenne steroid patient profiles with those of others who chronically used steroids. The Duchenne was clearly different. This makes it more likely that the profile is Duchenne specific.

However it is still troubling that without steroids the patient profiles clustered with controls. It is possible the profiles of Duchenne and other steroid users was due to the pathology of the other patients (not sure if authors looked into this). So I am not yet fully convinced. Also think the epigenetic profile of muscle would be more interesting but understand the challenges of obtaining muscle samples from patients and controls.

Authors tried to correlate the profiles with functional and disease milestones but found nothing significant. Likely this is due to the small sample size. As always more work is needed to unequivocally show the epigenetic profile is Duchenne specific (or rather identify what is due to Duchenne and what is due to steroids).