Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma

Davenport, Colin; Scheithauer, Tobias; Dunst, Alessia; Bahr, Frauke Sophie; Dorda, Marie; Wiehlmann, Lutz; Tran, Doan Duy Hai

doi:10.3390/ijms22083937

Cited by 14 publications

(10 citation statements)

References 70 publications

(56 reference statements)

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“…As shown by the Kaplan-Meier plot ( p -value<0.05), 11 genes were significantly associated with overall survival of patients ( Supplementary File S1 ). Downregulation of tumor suppressor genes function importantly in cancer formation and progression, which involves alteration of epigenetic modifications in genome-wide ( Davenport et al, 2021 ). Combined with transcriptome, six genes could be regarded as tumor suppressor genes ( Figure 5 ).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Analysis of DNA 5-Methylcytosine and N6-Adenine Methylation by Nanopore Sequencing in Hepatocellular Carcinoma

Zhang

Rong

et al. 2022

Front. Cell Dev. Biol.

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DNA methylation is a widespread epigenetic signal in human genome. With Nanopore technology, differential methylation modifications including 5-methylcytosine (5mC) and 6-methyladenine (6mA) can be identified. 5mC is the most important modification in mammals, although 6mA may also function in growth and development as well as in pathogenesis. While the role of 5mC at CpG islands in promoter regions associated with transcriptional regulation has been well studied, but the relationship between 6mA and transcription is still unclear. Thus, we collected two pairs of tumor tissues and adjacent normal tissues from hepatocellular carcinoma (HCC) surgical samples for Nanopore sequencing and transcriptome sequencing. It was found that 2,373 genes had both 5mC and 6mA, along with up- and down-regulated methylation sites. These genes were regarded as unstable methylation genes. Compared with 6mA, 5mC had more inclined distribution of unstable methylation sites. Chi-square test showed that the levels of 5mC were consistent with both up- and down-regulated genes, but 6mA was not significant. Moreover, the top three unstable methylation genes, TBC1D3H, CSMD1, and ROBO2, were all related to cancer. Transcriptome and survival analyses revealed four potential tumor suppressor genes including KCNIP4, CACNA1C, PACRG, and ST6GALNAC3. In this study, we firstly proposed to combine 5mC and 6mA methylation sites to explore functional genes, and further research found top of these unstable methylation genes might be functional and some of them could serve as potential tumor suppressor genes. Our study provided a new solution for epigenetic regulation research and therapy of HCC.

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Section: Resultsmentioning

confidence: 99%

Comprehensive Analysis of DNA 5-Methylcytosine and N6-Adenine Methylation by Nanopore Sequencing in Hepatocellular Carcinoma

Zhang

Rong

et al. 2022

Front. Cell Dev. Biol.

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“…Recent data identified 161 putative driver genes that are associated with 11 recurrently altered pathways in HCC development [ 4 ], and these mutations were not observed in chronic hepatitis or cirrhosis (preneoplastic stages). Interestingly, 28% of the altered gene products play a role in chromatin remodeling, suggesting that abnormal chromatin remodeling results in a cancer-specific expression of a subset of genes [ 7 , 8 , 26 ]. Indeed, DNase-seq data which map the chromatin accessibility revealed that chromatin at the putative promotor region of seven out of nine HCC-specific lincRNAs is opened in HCC but not in normal liver ( Figure 1 B).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Micropeptides Derived from Hepatocellular Carcinoma-Specific Long Noncoding RNA

Polenkowski

Lara

Allister

et al. 2021

IJMS

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Identification of cancer-specific target molecules and biomarkers may be useful in the development of novel treatment and immunotherapeutic strategies. We have recently demonstrated that the expression of long noncoding (lnc) RNAs can be cancer-type specific due to abnormal chromatin remodeling and alternative splicing. Furthermore, we identified and determined that the functional small protein C20orf204-189AA encoded by long intergenic noncoding RNA Linc00176 that is expressed predominantly in hepatocellular carcinoma (HCC), enhances transcription of ribosomal RNAs and supports growth of HCC. In this study we combined RNA-sequencing and polysome profiling to identify novel micropeptides that originate from HCC-specific lncRNAs. We identified nine lncRNAs that are expressed exclusively in HCC cells but not in the liver or other normal tissues. Here, DNase-sequencing data revealed that the altered chromatin structure plays a key role in the HCC-specific expression of lncRNAs. Three out of nine HCC-specific lncRNAs contain at least one open reading frame (ORF) longer than 50 amino acid (aa) and enriched in the polysome fraction, suggesting that they are translated. We generated a peptide specific antibody to characterize one candidate, NONHSAT013026.2/Linc013026. We show that Linc013026 encodes a 68 amino acid micropeptide that is mainly localized at the perinuclear region. Linc013026-68AA is expressed in a subset of HCC cells and plays a role in cell proliferation, suggesting that Linc013026-68AA may be used as a HCC-specific target molecule. Our finding also sheds light on the role of the previously ignored ’dark proteome’, that originates from noncoding regions in the maintenance of cancer.

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“…It shows the need for single-cell epigenetic technology capacity to truck drug-induced tumor evolution for the timely intercession of the treatment [ 293 ]. In hepatocellular carcinoma, identification of the modification status of tumor suppressor genes using nanopore sequencing showed around 10 potential tumor suppressor gene candidates and the glucokinase gene, more validated to involve in HCC development [ 375 ]. Nanopore sequencing allows whole-genome sequencing with the possible identification of epigenetic modifications in lung cancer cell line LC2/ad gene [ 376 ].…”

Section: Nanopore Sequencing For Epigenetic Tumor Heterogeneitymentioning

confidence: 99%

Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing

et al. 2022

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Nanopore sequencing has brought the technology to the next generation in the science of sequencing. This is achieved through research advancing on: pore efficiency, creating mechanisms to control DNA translocation, enhancing signal-to-noise ratio, and expanding to long-read ranges. Heterogeneity regarding epigenetics would be broad as mutations in the epigenome are sensitive to cause new challenges in cancer research. Epigenetic enzymes which catalyze DNA methylation and histone modification are dysregulated in cancer cells and cause numerous heterogeneous clones to evolve. Detection of this heterogeneity in these clones plays an indispensable role in the treatment of various cancer types. With single-cell profiling, the nanopore sequencing technology could provide a simple sequence at long reads and is expected to be used soon at the bedside or doctor’s office. Here, we review the advancements of nanopore sequencing and its use in the detection of epigenetic heterogeneity in cancer.

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Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma

Cited by 14 publications

References 70 publications

Comprehensive Analysis of DNA 5-Methylcytosine and N6-Adenine Methylation by Nanopore Sequencing in Hepatocellular Carcinoma

Comprehensive Analysis of DNA 5-Methylcytosine and N6-Adenine Methylation by Nanopore Sequencing in Hepatocellular Carcinoma

Identification of Novel Micropeptides Derived from Hepatocellular Carcinoma-Specific Long Noncoding RNA

Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing

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