Transcript overexpression of theMBD2andMBD4genes in CD4+ T cells from systemic lupus erythematosus patients

Abstract

Global DNA hypomethylation in CD4+ T cells has been detected in systemic lupus erythematosus (SLE), and it seems to be linked to its pathogenesis. We investigated the relationship between overall DNA methylation and the expression of two methyl CpG-binding domain (MBD) proteins. DNA deoxymethylcytosine (d(m)C) content of purified CD4(+) T cells from 29 SLE patients and 30 healthy controls was measured by means of an ELISA. Transcript levels of two methyl CpG-binding proteins (MBD2 and MBD4) were quantified by real-time RT-PCR. Association studies were also carried out with several laboratory parameters, as well as with the patients' clinical manifestations. SLE patients had significantly less CD4+ T cell DNA d(m)C content than controls (0.802+/-0.134 vs. 0.901+/-0.133; P=0.007). MBD2 and MBD4 mRNA levels were considerably higher in the patients' group: 0.975 +/- 0683 versus 0.604 +/- 0.614 (P=0.004) and 0.359 +/- 0.330 versus 0.092 +/- 0.169, respectively (P<0.0005). It is interesting that SLE patients showed a negative correlation between methylation indices and MBD2 (r=-0.609, P<0.0005) and MBD4 (r=-0.395, P=0.034) transcript levels. MBD2 and MBD4 transcript overexpression and inverse correlations with DNA methylation indices indicate that both enzymes may really have a direct and active role on the genome-wide DNA hypomethylation observed in CD4+ T cells from SLE patients.

Dynamic changes in global and gene specific DNA methylation during hibernation in adult thirteen-lined ground squirrels,Ictidomys tridecemlineatus

“…These proteins can be present in varying amounts that do not necessarily rely on the abundance of genomic methylation; for example, MBD2 and MBD4 are overexpressed in CD4+ T-cells that exhibit genomic hypomethylation in erythematosus lupus (Balada et al, 2007). MBDs can act in both repressor (Klose and Bird, 2006;Ng et al, 1999) and activator (Baubec et al, 2013;Bhattacharya et al, 1999;Brown and Szyf, 2007) roles.…”

Mbd2 Promotes Foxp3 Demethylation and T-Regulatory-Cell Function

“…Surprisingly, it has been proposed that one well-characterized 44-kDa Mbd protein, Mbd2, may act as a DNA demethylase by removing repressive methyl residues and thereby activating gene transcription (4). Overexpression of Mbd2 can activate gene expression as a result of demethylation of CpG islands within promoter regions (5), and correlations between high levels of Mbd2 and DNA demethylation were reported in several autoimmune diseases, including systemic lupus erythematosus (SLE), dermatomyositis and systemic sclerosis (6)(7)(8), rheumatoid arthritis (9), and psoriasis (10), as well as in breast cancer (11). However, other groups have failed to detect any demethylation activity of Mbd2 (12)(13)(14), and so it remains controversial as to whether Mbd2 itself has direct demethylase activity.…”

Epigenetics and Autoimmunity, with Special Emphasis on Methylation

“…31,34,35 Variations have also been described in histones of CD4 + T cells from patients with SLE. 3 6 In particular, H3 and H4 acetylation levels have been shown to correlate negatively with disease activity.…”