DNA methylation signatures of the AIRE promoter in thymic epithelial cells, thymomas and normal tissues

Kont, Vivian; Murumägi, Astrid; Tykocinski, Lars-Oliver; Kinkel, Sarah; Webster, Kylie E.; Kisand, Kai; Tserel, Liina; Pihlap, Maire; Ströbel, Philipp; Scott, Hamish S.; Marx, Alexander; Kyewski, Bruno; Peterson, Pärt

doi:10.1016/j.molimm.2011.09.022

Cited by 30 publications

(22 citation statements)

References 33 publications

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“…Furthermore, cis-acting binding sites for activator protein-1, specificity protein-1, nuclear factor Y, and Ets have been identified (33). Evidence that CpG methylation plays a role in regulating AIRE gene expression has emerged (34,35) The current studies reveal that AIRE expression in fibrocytes can be attributed to an active gene promoter ( Figure 2B). The molecular basis for the constitutively active AIRE gene promoter in fibrocytes will require further study.…”

Section: Discussionmentioning

confidence: 60%

Expression of Thyrotropin Receptor, Thyroglobulin, Sodium-Iodide Symporter, and Thyroperoxidase by Fibrocytes Depends on AIRE

Fernando

Atkins

et al. 2014

The Journal of Clinical Endocrinology &Amp; Metabolism

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Section: Discussionmentioning

confidence: 60%

Expression of Thyrotropin Receptor, Thyroglobulin, Sodium-Iodide Symporter, and Thyroperoxidase by Fibrocytes Depends on AIRE

Fernando

Atkins

et al. 2014

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…For example, it is known that the autoimmune regulator ( AIRE ) gene is hypomethylated in thymomas, and that both DNA and histone tail methylation marks regulate AIRE expression [31]. Therefore, we speculate that MTHFR methylation contributes to both DNA and histone tail methylation changes; however, this must be demonstrated in subsequent studies.…”

Section: Discussionmentioning

confidence: 84%

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Lopomo

Ricciardi

Maestri

et al. 2016

IJMS

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Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood.

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“…For mTEC cell isolation, we used a modified version of the Kont protocol (41). In this protocol, magnetic microbeads are used for cell isolation, and the purity is determined by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells

et al. 2016

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Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not) to small-interfering-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA–mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire-knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire-knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA–mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3′ UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA–mRNA network controlling PTAs in mTEC cells.

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DNA methylation signatures of the AIRE promoter in thymic epithelial cells, thymomas and normal tissues

Cited by 30 publications

References 33 publications

Expression of Thyrotropin Receptor, Thyroglobulin, Sodium-Iodide Symporter, and Thyroperoxidase by Fibrocytes Depends on AIRE

Expression of Thyrotropin Receptor, Thyroglobulin, Sodium-Iodide Symporter, and Thyroperoxidase by Fibrocytes Depends on AIRE

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells

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