Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes
Genome-wide loss of DNA methylation is commonly observed in human cancers, but its impact on the tumor transcriptome remains ill-defined. Previous studies demonstrated that this epigenetic alteration causes aberrant activation of a germline-specific gene expression program. Here, we examined if DNA...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/4/1007 |
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| author | Anna Diacofotaki Axelle Loriot Charles De Smet |
| author_facet | Anna Diacofotaki Axelle Loriot Charles De Smet |
| author_sort | Anna Diacofotaki |
| collection | DOAJ |
| description | Genome-wide loss of DNA methylation is commonly observed in human cancers, but its impact on the tumor transcriptome remains ill-defined. Previous studies demonstrated that this epigenetic alteration causes aberrant activation of a germline-specific gene expression program. Here, we examined if DNA hypomethylation in tumors also leads to de-repression of gene clusters with other tissue specificities. To this end, we explored transcriptomic and methylomic datasets from human lung adenocarcinoma (LUAD) cell lines, normal lung, and lung alveolar type II cells, considered as the origin of LUAD. Interestingly, DNA demethylation in LUAD cell lines was associated with activation of not only germline-specific (CG) genes, but also gene clusters displaying specific expression in the gastrointestinal tract (GI), or in stratified epithelia (SE). Consistently, genes from all three clusters showed highly specific patterns of promoter methylation among normal tissues and cell types, and were generally sensitive to induction by a DNA demethylating agent. Analysis of TCGA datasets confirmed that demethylation and activation of CG, GI and SE genes also occurs in vivo in LUAD tumor tissues, in association with global genome hypomethylation. For genes of the GI cluster, we demonstrated that HNF4A is a necessary factor for transcriptional activation following promoter demethylation. Interestingly, expression of several SE genes, in particular <i>FAM83A</i>, correlated with both tumor grade and reduced patient survival. Together, our study uncovers novel cell-type specific gene clusters that become aberrantly activated in LUAD tumors in association with genome-wide hypomethylation. |
| first_indexed | 2024-03-09T22:23:33Z |
| format | Article |
| id | doaj.art-d7b6764e1e4c4a0a85cb9094eb84537c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T22:23:33Z |
| publishDate | 2022-02-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d7b6764e1e4c4a0a85cb9094eb84537c2023-11-23T19:09:53ZengMDPI AGCancers2072-66942022-02-01144100710.3390/cancers14041007Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline GenesAnna Diacofotaki0Axelle Loriot1Charles De Smet2Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, BelgiumGroup of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, BelgiumGroup of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, BelgiumGenome-wide loss of DNA methylation is commonly observed in human cancers, but its impact on the tumor transcriptome remains ill-defined. Previous studies demonstrated that this epigenetic alteration causes aberrant activation of a germline-specific gene expression program. Here, we examined if DNA hypomethylation in tumors also leads to de-repression of gene clusters with other tissue specificities. To this end, we explored transcriptomic and methylomic datasets from human lung adenocarcinoma (LUAD) cell lines, normal lung, and lung alveolar type II cells, considered as the origin of LUAD. Interestingly, DNA demethylation in LUAD cell lines was associated with activation of not only germline-specific (CG) genes, but also gene clusters displaying specific expression in the gastrointestinal tract (GI), or in stratified epithelia (SE). Consistently, genes from all three clusters showed highly specific patterns of promoter methylation among normal tissues and cell types, and were generally sensitive to induction by a DNA demethylating agent. Analysis of TCGA datasets confirmed that demethylation and activation of CG, GI and SE genes also occurs in vivo in LUAD tumor tissues, in association with global genome hypomethylation. For genes of the GI cluster, we demonstrated that HNF4A is a necessary factor for transcriptional activation following promoter demethylation. Interestingly, expression of several SE genes, in particular <i>FAM83A</i>, correlated with both tumor grade and reduced patient survival. Together, our study uncovers novel cell-type specific gene clusters that become aberrantly activated in LUAD tumors in association with genome-wide hypomethylation.https://www.mdpi.com/2072-6694/14/4/1007epigeneticsDNA methylationDNA hypomethylationcancer-germline geneslung adenocarcinoma |
| spellingShingle | Anna Diacofotaki Axelle Loriot Charles De Smet Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes Cancers epigenetics DNA methylation DNA hypomethylation cancer-germline genes lung adenocarcinoma |
| title | Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes |
| title_full | Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes |
| title_fullStr | Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes |
| title_full_unstemmed | Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes |
| title_short | Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes |
| title_sort | identification of tissue specific gene clusters induced by dna demethylation in lung adenocarcinoma more than germline genes |
| topic | epigenetics DNA methylation DNA hypomethylation cancer-germline genes lung adenocarcinoma |
| url | https://www.mdpi.com/2072-6694/14/4/1007 |
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