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Transcriptional overlap mediates epigenetic Swapping of AGO1 isoforms in tumors

Denoue, Claudia
(2024)

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Denoue_49731800_2024.pdf
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Details

Supervisors
De Smet, Charles
Faculty
Faculté de médecine et médecine dentaire
Degree label
Master [180] en médecine, à finalité spécialisée
Abstract
Our laboratory has demonstrated that certain tumoral cells exhibit the activation of a specific subset of genes known as cancer-germline genes, facilitated by hypomethylation of their promoter regions. This activation coincides with the silencing of a downstream gene through hypermethylation of its promotor, indicating a dual hypo/hypermethylation process in cancer cells. Through analysis of transcriptomic and methylomic data, we identified a gene, termed AGO1-V2, exhibiting characteristics akin to cancer-germline genes. AGO1-V2 overlaps with the transcription of the Argonaute 1 gene, which encodes the Argonaute 1 protein, famously known for its role in gene expression regulation. After providing evidence for AGO1-V2’s cancer-germline chatacteristics in vivo, our objective is to further characterize this transcript by investigating whether it encodes a truncated form of AGO1 given their similar open reading frames. Addi1onally, we seek to determine its cellular localization and assess the impact of its depletion on cell growth in tumoral cells. Our findings reveal that AGO1-V2 effectively codes for two truncated proteins in lung adenocarcinoma cells. Through cellular fractionation studies and immunofluorescence techniques, we observe predominant localization within the granular subcellular compartment of the cytoplasm. However, CRISPR-Cas9 genomic editing, inducing knockouts of both genes in these tumoral cells, demonstrates no significant effect on cell growth. By delving into the characterization of this cancer-germline gene, we uncover valuable insights into its oncogenic traits, potentially hinting at its participation in RNA interference post-transcriptionally. Additionally, we highlight the correlation between genomic hypomethylation and hypermethylation of pivotal genes implicated in tumorigenesis, further clarifying the role of methylation in tumor development. Armed with these insights, we aim to contribute to the understanding of this gene's role, paving the way for its effective utilization as a therapeutic target in tumor treatments.