The enzyme EZH2 is present in higher-than-normal levels in fibroblasts and endothelial cells from scleroderma patients, a study shows, and suggests blocking or inhibiting EZH2 to prevent fibrosis and restore normal blood vessel formation.
The study, “Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma,” was published in the journal PNAS.
Evidence so far suggests that scleroderma’s development depends on many factors, with epigenetic mechanisms gaining attention for their involvement in the disease. Epigenetic alterations consist in changes in the cell’s DNA to control DNA expression, but without changing the genetic sequence itself. The control is over the proteins that are being produced.
Researchers at Michigan University Ann Harbor explored how EZH2, an enzyme that controls epigenetic mechanisms, is implicated in scleroderma.
The team first looked at the expression of EZH2 in tissue samples from scleroderma patients and healthy individuals.
Analysis revealed that the levels of EZH2, at the messenger RNA level (the molecule containing the genetic information from the DNA, and needed for protein production), were significantly higher in patients with diffuse cutaneous form of scleroderma compared to those with the limited cutaneous form, or to healthy individuals.
At the protein level, EZH2 was also present in significantly higher levels in skin fibroblasts and in endothelial cells forming blood vessels in scleroderma samples.
Treatment of scleroderma-derived fibroblasts with DZNep, an EZH2 inhibitor, led to changes in the activity of genes involved in both fibrosis and blood vessel formation (a process known as angiogenesis).
Moreover, treatment with DZNep led to epigenetic changes. Specifically, out of 24 genes, 13 became hypermethylated — meaning they had more epigenetic marks, in this case methyl groups, that led to gene silencing (no gene activity).
One of these hypermethylated genes was LRRC16A.
Fibroblasts in scleroderma are known to have an increased migratory capacity, but treating fibroblasts with DZNep lowered cell migration. Moreover, increasing the levels (overexpression) of EZH2 in normal fibroblasts led to enhanced migration similar to that observed in scleroderma. This was reversed by decreasing the levels of the LRRC16A gene, suggesting that LRRC16A is involved in EZH2-mediated cell migration.
Next, the researchers tested how EZH2 affected endothelial cells, whose function is compromised in scleroderma. They found that when EZH2 is overexpressed, it inhibits angiogenesis, while removing EZH2 results in a greater angiogenesis capacity.
“We identified EZH2 as a key epigenetic regulator that promotes fibrosis and inhibits angiogenesis in scleroderma,” researchers wrote, adding that LRRC16A “is a mediator for EZH2-induced cell migration in scleroderma fibroblasts.”
The team demonstrated that angiogenesis inhibition was linked to the disruption of Notch pathway genes, which are involved in angiogenesis. Particularly, the DLL4 gene is repressed by EZH2, and when cells are treated with an inhibitor like DZNep they show higher expression of this notch ligand.
“We revealed that EZH2-Notch axis controls angiogenesis through the Notch ligand DLL4 in scleroderma. These findings suggest a role for utilizing EZH2 inhibitors to treat scleroderma,” the researchers concluded.
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