Pan-cancer predictions of transcription factors mediating aberrant DNA methylation

Detilleux, Dylane; Spill, Yannick G.; Balaramane, Delphine; Weber, Michaël; Bardet, Anaïs F.

doi:10.1186/s13072-022-00443-w

Cited by 15 publications

(10 citation statements)

References 67 publications

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“…6 B, bottom panel), with low DNA methylation at their regulatory regions in GIV gliomas (Chi-square test for two independent groups, FDR < 0.05). A similar relation was found in other cancers [ 31 ]. Methylation of a specific cytosine within a c-Jun motif instance (1 cytosine in the c-Jun motif, “dvTGAGTCAYh”, HOCOMOCO version 11) within the promoters of putative c-Jun targets was found.…”

Section: Resultssupporting

confidence: 88%

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

et al. 2023

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Background Glioblastoma (GBM, WHO grade IV) is an aggressive, primary brain tumor. Despite extensive tumor resection followed by radio- and chemotherapy, life expectancy of GBM patients did not improve over decades. Several studies reported transcription deregulation in GBMs, but regulatory mechanisms driving overexpression of GBM-specific genes remain largely unknown. Transcription in open chromatin regions is directed by transcription factors (TFs) that bind to specific motifs, recruit co-activators/repressors and the transcriptional machinery. Identification of GBM-related TFs-gene regulatory networks may reveal new and targetable mechanisms of gliomagenesis. Results We predicted TFs-regulated networks in GBMs in silico and intersected them with putative TF binding sites identified in the accessible chromatin in human glioma cells and GBM patient samples. The Cancer Genome Atlas and Glioma Atlas datasets (DNA methylation, H3K27 acetylation, transcriptomic profiles) were explored to elucidate TFs-gene regulatory networks and effects of the epigenetic background. In contrast to the majority of tumors, c-Jun expression was higher in GBMs than in normal brain and c-Jun binding sites were found in multiple genes overexpressed in GBMs, including VIM, FOSL2 or UPP1. Binding of c-Jun to the VIM gene promoter was stronger in GBM-derived cells than in cells derived from benign glioma as evidenced by gel shift and supershift assays. Regulatory regions of the majority of c-Jun targets have distinct DNA methylation patterns in GBMs as compared to benign gliomas, suggesting the contribution of DNA methylation to the c-Jun-dependent gene expression. Conclusions GBM-specific TFs-gene networks identified in GBMs differ from regulatory pathways attributed to benign brain tumors and imply a decisive role of c-Jun in controlling genes that drive glioma growth and invasion as well as a modulatory role of DNA methylation.

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Section: Resultssupporting

confidence: 88%

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

et al. 2023

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“…The methylation pattern of the promoters of other c-Jun target genes clearly differed (Fig. 6B, bottom panel) with low DNA methylation at their regulatory regions in GIV gliomas (Chi-square test for two independent groups, FDR<0.05), also observed in other types of human cancer [31]. Methylation of a specific cytosine within a c-Jun motif instance (1 cytosine in the c-Jun motif, “dvTGAGTCAYh”, HOCOMOCO version 11) within the promoters of the potential c-Jun targets was found.…”

Section: Resultsmentioning

confidence: 99%

Section: Dna Methylation At the Promoters Of C-jun Putative Targets D...mentioning

confidence: 92%

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Roura

Szadkowska

Poleszak

et al. 2022

Preprint

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BackgroundGlioblastoma (GBM, WHO grade IV) is an aggressive, primary brain tumor. Despite gross surgery and forceful radio- and chemotherapy, survival of GBM patients did not improve over decades. Several studies reported transcription deregulation in GBMs but regulatory mechanisms driving overexpression of GBM-specific genes remain largely unknown. Transcription in open chromatin regions is directed by transcription factors (TFs) that bind to specific motifs, recruit co-activators/repressors and the transcriptional machinery. Identification of GBM-related TFs-gene regulatory networks may reveal new and targetable mechanisms of gliomagenesis.ResultsWe predicted TFs-regulated networks in GBMs in silico and intersected them with putative TF binding sites identified in the accessible chromatin in human glioma cells and GBM patient samples. The Cancer Genome Atlas and Glioma Atlas datasets (DNA methylation, H3K27 acetylation, transcriptomic profiles) were explored to elucidate TFs-gene regulatory networks and effects of the epigenetic background. In contrast to the majority of tumors, c-Jun expression was higher in GBMs than in normal brain and c-Jun binding sites were found in multiple genes overexpressed in GBMs such as VIM, FOSL2 or UPP1. Binding of c-Jun to the VIM gene promoter is stronger in GBM cells than in cells derived from benign glioma as evidenced by gel shift and supershift assays. Regulatory regions of a majority of the c-Jun targets have distinct DNA methylation in GBMs suggesting the contribution of DNA methylation to the c-Jun-dependent regulation.ConclusionsWe identified distinct TFs-gene networks in GBMs compared to benign gliomas, a predominant role of c-Jun in controlling genes driving gliomagenesis and a modulatory role of DNA methylation.

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“…Abnormal DNA methylation is highly associated with the incidence and growth of tumors [31]. Previous studies have shown that RBM10 is related to DNA methylation [32,33].…”

Section: Discussionmentioning

confidence: 99%

RBM10 Is a Biomarker Associated with Pan-Cancer Prognosis and Immune Infiltration: System Analysis Combined with In Vitro and Vivo Experiments

Cao

Pang

Shi

2022

Oxidative Medicine and Cellular Longevity

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RNA binding motif protein 10 (RBM10) is a splicing factor that has been reported to be involved in the occurrence and progression of multiple malignancies. However, the RBM10 involvement in pan-cancer immunotherapy is not clear. In here, we provide the first comprehensive assessment of the prognostic value and immunological function of RBM10 in human pan-cancer utilizing multiple public databases. Data reveal the aberrant RBM10 expression in most tumors, and its expression is positively or negatively linked with the clinical prognosis of various cancers, depending on the different types and subtypes of cancers. In most tumors, RBM10 mutations are frequently occurred, which is closely related to tumor progression. Moreover, our results also show that RBM10 is considerably linked with most of the immune checkpoint genes, tumor immune cell infiltration, tumor mutation burden, and microsatellite instability. Additionally, RBM10 is significantly positively correlated with the sensitivity of trametinib, 17-AAG, PD-0325901, RDEA119, cetuximab, and afatinib, indicating potential antagonism between RBM10 inhibitors and these antitumor drugs, and more likely to develop drug resistance. We also verify that downregulation of RBM10 enhances the malignant phenotype of lung adenocarcinoma cells using in vitro cell experiments, and in vivo animal experiments show that the overexpression of RBM10 reduces the growth of tumors. Furthermore, upregulating RBM10 greatly reduces the PD-L1 protein levels, while silencing RBM10 considerably enhances PD-L1 protein levels. Moreover, the overexpression of RBM10 decreases the protein stability of PD-L1. To sum up, our pan-cancer analysis indicates that RBM10 is a promising biomarker for prognosis and immunotherapy, which provides a new insight for cancer immunotherapy.

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Pan-cancer predictions of transcription factors mediating aberrant DNA methylation

Cited by 15 publications

References 67 publications

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

RBM10 Is a Biomarker Associated with Pan-Cancer Prognosis and Immune Infiltration: System Analysis Combined with In Vitro and Vivo Experiments

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