Unknown,Transcriptomics,Genomics,Proteomics

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Aberrant Methylated DNA Regions Lead to Low Activation of CD4+ T Cells with a Consequent Imbalance of the Th1/Th2 Polarization in IgA Nephropathy Patients

ABSTRACT: To investigate alterations in the DNA methylation of CD4+ T cells in IgA nephropathy (IgAN), we performed an initial whole-genome DNA methylation screening on CD4+ T cells isolated from 6 IgAN patients and 6 healthy subjects (HS). We analyzed more than 485000 CpGs targeted across their promoters, 5'-untranslated regions (UTRs), first exons, gene bodies and 3'UTRs. Some of the most significant differentially methylated regions included genes specifically expressed in T cells and involved in the T cell receptor signaling. In particular, we found hypomethylation in the promoter region of DUSP3 and in the 3âUTR of TRIM27 (chr17:41840001-41845000; âÎ²= -0.39; chr6:28876508-28893266; âÎ²= -0.31). The products of these genes function as signal transductors of the T cell receptor. Moreover, in the chromosome 5 (chr5:135416205-135416475) we found the most strongly and extensively hypermethylated region in IgAN patients respect to HS (âÎ²=0.31) in the promoter region of VTRNA2-1 gene (known as precursor microRNA miR-886). The methylated region, 200 bp upstream of the transcription start site, it is also part of a CpG island. Bisulfite-converted DNA from the 12 samples (CD4+ T cells from 6 IgAN patients and 6 healthy subjects) were hybridised to the Illumina Infinium HumanMethylation450 BeadChip.

ORGANISM(S): Homo sapiens

SUBMITTER: Fabio Sallustio

PROVIDER: E-GEOD-72364 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Immunoglobulin A Nephropathy (IgAN) is a complex multifactorial disease whose genetic bases remain unknown. Distinct linkage and genome-wide association studies in both familial and sporadic IgAN suggest that there is a strong genetic component in IgAN. In this context, an intriguing role could be ascribed to copy number variants (CNVs) that have been recognized as an important source of genetic variation in humans. Here, we performed a whole-genome screening of CNVs in IgAN patients, their healthy relatives and healthy subjects (HS). A total of 217 individuals consisting of 51 IgAN cases and 166 healthy relatives were included in the initial screening. The high-throughput analysis of structural genetic variations, to find concordant aberrations across classes of samples, identified 178 IgAN-specific aberrations, specifically 114 loss and 64 gain. Several CNVs overlapped with regions evidenced by previous genome-wide genetic studies. Moreover, we found that IgAN patients characterized by deteriorated renal function carried low copy numbers of a CNV in chromosome 3 (chr3_loss:52031010-52260722). This CNV contained the TLR9 gene whose expression significantly correlated with the loss aberration in patients with progressive renal damage. Conversely, IgAN patients with normal renal function had no chr3_loss:52031010-52260722 and the TLR9 mRNA was expressed at the same level as in HS, still maintaining a strong correlation with the CNV. In conclusion, here we performed the first genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease. Moreover, we identified a specific CNV, spanning the TLR9 gene, which could explain the disease severity in IgAN patients. To perform a genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease.

Dataset Information

Aberrant Methylated DNA Regions Lead to Low Activation of CD4+ T Cells with a Consequent Imbalance of the Th1/Th2 Polarization in IgA Nephropathy Patients

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