Background/Purpose: Foxp3 is the signature transcription factor of regulatory T cells (Tregs) and facilitates many of the characteristic functions of Tregs. Members of the Ikaros family of transcription factors have been implicated in controlling the phenotype of Tregs, in part by interacting with Foxp3. Ikaros family zinc finger 4 (IKZF4, Eos) mediates Foxp3-dependent gene silencing and is required to maintain the phenotype of Foxp3-positive Tregs, whereas IKFZ2 (Helios) is involved in the suppression of IL2 gene transcription and upregulation of Foxp3. An important regulation level of tissue-specific geneexpression is DNA methylation. In particular, Treg-specific gene expression is controlled by DNA methylation within characteristic clusters, Treg-specific demethylation regions.

Methods: To analyze the DNA methylation status of Treg-specific demethylated regions (TSDR) of Foxp3, Helios and Eos in T cells from patients with rheumatoid arthritis (RA) and to compare the level of methylation to that in T cells from healthy controls.

Results: All analyzed regions were completely methylated in effector T cells from RA patients and controls. In contrast, considerable degrees of demethylation were detected in the regions of interest in CD25+CD127- T cells, in line with the hypothesis of an important regulatory mechanism facilitating Treg-specific gene expression. No differences were detected between Tregs from RA patients and controls with regard to the level of methylation within the TSDR of FoxP3. Importantly, the methylation rate of the CNS CpG island in the Helios gene was significantly higher in Tregs from RA patients than in those from controls (55% vs. 40%, p<0.05). Similarly, the CpGs within exon 6 of the Helios gene were demethylated to a significantly different level between RA patients and controls (50% vs. 40% methylation, respectively; p<0.05). Finally, in the CNS CpG island of the Eos gene, the methylation level in Tregs from RA patients was also significantly higher as compared to healthy control Tregs (68% vs. 53%, p<0.01).

Conclusion: The data are consistent with the hypothesis of Treg specific expression of Helios and Eos regulated by DNA methylation within Treg-specific demethylation regions. Furthermore, the data suggest that impaired function Tregs in RA might be related to an altered expression of Helios and Eos as a consequence of increased DNA methylation. This mechanism might provide a molecular epigenetic insight into the pathogenesis of autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hypermethylation-of-treg-specific-demethylated-regions-in-the-ikaros-transcription-factor-family-members-helios-and-eos-in-rheumatoid-arthritis-tregs/