Epigenetic alterations and ectopic activation of tissue-specific gene clusters in lung adenocarcinoma
(2022)
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- Authors
- Supervisors
- De Smet, Charles
- Abstract
- Tumor development is characterized by both genetic and epigenetic alterations that lead to gene expression changes. One of such transcriptomic changes is the aberrant activation of a group of germline-specific genes in a variety of tumors of somatic origin. The spurious activation of this group of genes is due to the DNA demethylation of their promoter region in tumor cells, a phenomenon associated with the global loss of DNA methylation that often accompanies tumorigenesis. Several of these “cancer-germline” genes were found to exert pro-tumoral functions, or evoke an immune response. Cancer-germline genes are therefore attracting much interest, as they constitute promising targets for anti-cancer therapies with the hope of limited side effects due to their highly restricted pattern of expression. Whether additional tissue-specific gene clusters become activated in tumors, be it by DNA demethylation or not, remains unanswered. Most studies, indeed, have used transcriptomic approaches that were biased towards testis-specific genes. In the present work, we aimed to fill this gap by combining omics data of lung adenocarcinoma (LUAD) tissues and cell lines, as well as normal lung and alveolar type II cells (AT2), the cells of origin of LUAD, without imposing any criteria of expression specificity to the ectopically activated genes we were looking for. We divided our work in two complementary axes. In the first part, we asked whether the global loss of DNA demethylation in tumors is also associated with the ectopic activation of somatic-specific gene clusters in LUAD. We found that, indeed, promoter DNA demethylation in these cells leads to the transcriptional induction of genes displaying selective expression in gastro-intestinal tissues (colon and small intestine), and of genes specific to stratified squamous epithelia (esophagus, skin and vagina). Interestingly, our data show that ectopic activation of this latter group of genes in LUAD is associated with poor prognosis of the cancer patients. In the second part of our work, we assessed the extent of tissue-specific gene clusters that become ectopically activated in LUAD, irrespective of the regulatory mechanism involved in their activation, i.e., not especially as a result of DNA demethylation. The results revealed that besides the above identified tissue-specific gene clusters, a large number of brain-related genes were ectopically activated in LUAD tissues and cell lines. Multiple regulatory mechanisms appeared to contribute to the ectopic activation of these brain-related genes in LUAD, including ASCL1-driven neuroendocrine differentiation, promoter DNA demethylation, and dysregulation of the REST silencing complex. Our work confirms and extends previous observations of illegitimate transcription of germline and somatic-specific gene clusters in LUAD. We also shed light on the regulatory mechanisms involved in their aberrant activation, that contribute thereby to the “cellular identity crisis” of tumor cells.
- Affiliations
Citations
Diacofotaki, A. (2022). Epigenetic alterations and ectopic activation of tissue-specific gene clusters in lung adenocarcinoma. https://hdl.handle.net/2078.5/27586