Identification of a novel cancer-germline transcript within the miRNA harboring GABRA3 gene : epigenetic alterations of the locus in tumors
(2017)
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- Authors
- Supervisors
- De Smet, Charles
- Abstract
- It is now well established that alterations in DNA methylation patterns contribute to tumor development. Both gains (DNA hypermethylation) and losses (DNA hypomethylation) of this repressive mark are observed in tumors. Our group demonstrated that DNA hypomethylation in tumors induces transcriptional activation of a defined group of genes, which normally show specific expression in the germline. These genes were grouped under the term "cancer-germline" genes (CG genes). The main goal of the laboratory is to characterize the epigenetic regulation and functional roles of CG genes. Our work focused on the GABRA3 gene locus, where we discovered the existence of two overlapping transcripts: BT-GABRA3, which is expressed specifically in brain and testis; and CT-GABRA3, starting ~250 kb upstream, which is expressed exclusively in testis. CT-GABRA3 (but not BT-GABRA3) exhibits typical features of a CG gene, as it shows promoter hypomethylation and transcriptional activation in various tumors. CT-GABRA3 carries a clustered pair of miRNAs (miR-105 and miR-767), which show concurrent expression in tumors. Interestingly, an independent group identified miR-105 as a crucial promoter of cancer metastasis, due to its ability to weaken vascular endothelial barriers following exosomal secretion. On the other hand, we demonstrated that miR-767 inhibits expression of TET1, a gene with tumor suppressive functions involved in epigenetic processes of DNA demodification. Moreover, our studies revealed that CT-GABRA3 hypomethylation/activation in tumors is correlated with hypermethylation of the downstream BT-GABRA3 promoter. The mechanism underlying this interdependent epigenetic alteration appears to involve deposition of the histone mark H3K36me3 on the entire CT-GABRA3 transcribed region, which includes the BT-GABRA3 promoter. Finally, we observed that in tumor cells where the BT-GABRA3 promoter is hypermethylated, the gene becomes sensitive to DNA demethylation, suggesting a process of epigenetic switch. Together our work revealed the existence of a novel miRNA-producing CG gene with oncogenic potential. It also uncovered a unusual mechanism of epigenetic alteration in tumors, whereby DNA hypomethylation and hypermethylation are linked via a process of transcriptional overlap.
- Affiliations
Citations
Van Tongelen, A. (2017). Identification of a novel cancer-germline transcript within the miRNA harboring GABRA3 gene : epigenetic alterations of the locus in tumors. https://hdl.handle.net/2078.5/73559