Aberrantly methylated DNA regions in IgA Nephropathy patients affect the disease
The genome can influence the onset and the development of the diseases in several manner, and in the last years several studies have revealed the new role of the DNA methylation in this framework.
The DNA methylation is a mechanism that occurs by the addition of a methyl (CH3) group to DNA, thereby often modifying the function of the genes. This kind of mechanism (called epigenetic mechanism) does not change the DNA sequence but can alter how genes are read by cells. It can be caused by external or environmental factors.
In somatic cells, the methylation arises in correspondence to a CpG site, in which a cytosine nucleotide is located next to a guanidine nucleotide.When the promoter region of a gene is methylated, the expression of the gene is repressed.
The number of diseases influenced by the DNA methylation is progressively rising and comprises many common diseases such as schizophrenia, Alzheimer’s disease, diabetes, atherosclerosis, cancer, and so on.
The DNA methylation can be an important factor influencing also the IgA nephropathy (IgAN), that is the most common form of primary glomerulonephritis worldwide and has a strong genetic component. We performed a genome-wide screening for DNA methylation in CD4+ T-cells from IgAN patients in comparison with healthy subjects (HS). CD4+ T cells are particular cells of our immune system that are activated by antigens and are critical in the control of the antigen-driven adaptive immune response. Since the IgAN is an immunologically mediated disease, the CD4+ T-cells can influence this disease.
We found that the DNA methylation in IgAN patients influences the expression of some genes involved in the T-cell receptor signalling, the pathway that transfers the signal of the presence of antigens and that activates the T-cells. In particular, we found two genes, TRIM27 and DUSP3 hypo-methylated in correspondence of the promoter region that regulates their transcription. Effectively these genes, are up-regulated in CD4 T cells of IgAN patients.
Moreover, in the chromosome 5 we found the VTRNA2-1 gene region strongly and extensively hypermethylated. VTRNA2-1 belong to a novel class of non-coding RNA (nc-RNA) called vault RNA (VTRNA). As a consequence, the VTRNA2-1 expression level is significantly lower in CD4+ T-cells of IgAN patients. Thus, the hypermethylation of the VTRNA2-1 nc-RNA led to a decreased CD4+ T-cell proliferation.
In addition, this hypermethylated gene led also to the overexpression of TGFβ (transforming growth factor β). This is an important aspect of IgAN pathogenesis, since TGFβ1 plays a role in the immune-complex deposition at renal level, that is typical of this disease.
Besides, we found an imbalance of the T helper cells 1 and 2 in IgAN patients. The T helper cells modulate the immune response through their balance. This could be explained by the reduced TCR signal strength of the CD4+ T-cells and by their anomalous response and activation caused by the aberrant methylation.
In conclusion, this study reveals new molecular mechanisms underlying the abnormal CD4+ T-cell response in IgAN patients. The aberrantly methylated DNA regions of CD4+ T-cells in IgAN patients provide a means to better understand the molecular mechanisms involved in this disease and open up new perspectives in potential novel therapeutic targets for the treatment of the IgAN.
Fabio Sallustio, GraziaSerino and FP. Schena
University of Bari, Department of Emergency and Organ Transplantation
Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy.
Sallustio F, Serino G, Cox SN, Gassa AD, Curci C, De Palma G, Banelli B, Zaza G, Romani M, Schena FP.
Clin Sci (Lond). 2016 May 1