Monoallelic expression in melanoma
Abstract Background Monoallelic expression (MAE) is a frequent genomic phenomenon in normal tissues, however its role in cancer is yet to be fully understood. MAE is defined as the expression of a gene that is restricted to one allele in the presence of a diploid heterozygous genome. Constitutive MA...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12967-019-1863-x |
| _version_ | 1818338545756012544 |
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| author | Lee Silcock Hakeem Almabrazi Younes Mokrab Puthen Jithesh Muna Al-Hashmi Nicola James Rebecca Mathew Valentina Mattei Davide Bedognetti Francesca Lessi Ramzi Temanni Barbara Seliger Rashid Al-Ali Francesco M. Marincola Ena Wang Sara Tomei |
| author_facet | Lee Silcock Hakeem Almabrazi Younes Mokrab Puthen Jithesh Muna Al-Hashmi Nicola James Rebecca Mathew Valentina Mattei Davide Bedognetti Francesca Lessi Ramzi Temanni Barbara Seliger Rashid Al-Ali Francesco M. Marincola Ena Wang Sara Tomei |
| author_sort | Lee Silcock |
| collection | DOAJ |
| description | Abstract Background Monoallelic expression (MAE) is a frequent genomic phenomenon in normal tissues, however its role in cancer is yet to be fully understood. MAE is defined as the expression of a gene that is restricted to one allele in the presence of a diploid heterozygous genome. Constitutive MAE occurs for imprinted genes, odorant receptors and random X inactivation. Several studies in normal tissues have showed MAE in approximately 5–20% of the cases. However, little information exists on the MAE rate in cancer. In this study we assessed the presence and rate of MAE in melanoma. The genetic basis of melanoma has been studied in depth over the past decades, leading to the identification of mutations/genetic alterations responsible for melanoma development. Methods To examine the role of MAE in melanoma we used 15 melanoma cell lines and compared their RNA-seq data with genotyping data obtained by the parental TIL (tumor infiltrating lymphocytes). Genotyping was performed using the Illumina HumanOmni1 beadchip. The RNA-seq library preparation and sequencing was performed using the Illumina TruSeq Stranded Total RNA Human Kit and subsequently sequenced using a HiSeq 2500 according to manufacturer’s guidelines. By comparing genotyping data with RNA-seq data, we identified SNPs in which DNA genotypes were heterozygous and corresponding RNA genotypes were homozygous. All homozygous DNA genotypes were removed prior to the analysis. To confirm the validity to detect MAE, we examined heterozygous DNA genotypes from X chromosome of female samples as well as for imprinted and olfactory receptor genes and confirmed MAE. Results MAE was detected in all 15 cell lines although to a different rate. When looking at the B-allele frequencies we found a preferential pattern of complete monoallelic expression rather then differential monoallelic expression across the 15 melanoma cell lines. As some samples showed high differences in the homozygous and heterozygous call rate, we looked at the single chromosomes and showed that MAE may be explained by underlying large copy number imbalances in some instances. Interestingly these regions included genes known to play a role in melanoma initiation and progression. Nevertheless, some chromosome regions showed MAE without CN imbalances suggesting that additional mechanisms (including epigenetic silencing) may explain MAE in melanoma. Conclusion The biological implications of MAE are yet to be realized. Nevertheless, our findings suggest that MAE is a common phenomenon in melanoma cell lines. Further analyses are currently being undertaken to evaluate whether MAE is gene/pathway specific and to understand whether MAE can be employed by cancers to achieve a more aggressive phenotype. |
| first_indexed | 2024-12-13T15:12:49Z |
| format | Article |
| id | doaj.art-fd11d94296a64e7f83edce668d7c986b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-13T15:12:49Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-fd11d94296a64e7f83edce668d7c986b2022-12-21T23:40:49ZengBMCJournal of Translational Medicine1479-58762019-04-011711710.1186/s12967-019-1863-xMonoallelic expression in melanomaLee Silcock0Hakeem Almabrazi1Younes Mokrab2Puthen Jithesh3Muna Al-Hashmi4Nicola James5Rebecca Mathew6Valentina Mattei7Davide Bedognetti8Francesca Lessi9Ramzi Temanni10Barbara Seliger11Rashid Al-Ali12Francesco M. Marincola13Ena Wang14Sara Tomei15Sidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchFondazione Pisana Per la ScienzaSidra Medicine, Research BranchInstitute of Medical Immunology, Martin Luther University Halle-WittenbergSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchSidra Medicine, Research BranchAbstract Background Monoallelic expression (MAE) is a frequent genomic phenomenon in normal tissues, however its role in cancer is yet to be fully understood. MAE is defined as the expression of a gene that is restricted to one allele in the presence of a diploid heterozygous genome. Constitutive MAE occurs for imprinted genes, odorant receptors and random X inactivation. Several studies in normal tissues have showed MAE in approximately 5–20% of the cases. However, little information exists on the MAE rate in cancer. In this study we assessed the presence and rate of MAE in melanoma. The genetic basis of melanoma has been studied in depth over the past decades, leading to the identification of mutations/genetic alterations responsible for melanoma development. Methods To examine the role of MAE in melanoma we used 15 melanoma cell lines and compared their RNA-seq data with genotyping data obtained by the parental TIL (tumor infiltrating lymphocytes). Genotyping was performed using the Illumina HumanOmni1 beadchip. The RNA-seq library preparation and sequencing was performed using the Illumina TruSeq Stranded Total RNA Human Kit and subsequently sequenced using a HiSeq 2500 according to manufacturer’s guidelines. By comparing genotyping data with RNA-seq data, we identified SNPs in which DNA genotypes were heterozygous and corresponding RNA genotypes were homozygous. All homozygous DNA genotypes were removed prior to the analysis. To confirm the validity to detect MAE, we examined heterozygous DNA genotypes from X chromosome of female samples as well as for imprinted and olfactory receptor genes and confirmed MAE. Results MAE was detected in all 15 cell lines although to a different rate. When looking at the B-allele frequencies we found a preferential pattern of complete monoallelic expression rather then differential monoallelic expression across the 15 melanoma cell lines. As some samples showed high differences in the homozygous and heterozygous call rate, we looked at the single chromosomes and showed that MAE may be explained by underlying large copy number imbalances in some instances. Interestingly these regions included genes known to play a role in melanoma initiation and progression. Nevertheless, some chromosome regions showed MAE without CN imbalances suggesting that additional mechanisms (including epigenetic silencing) may explain MAE in melanoma. Conclusion The biological implications of MAE are yet to be realized. Nevertheless, our findings suggest that MAE is a common phenomenon in melanoma cell lines. Further analyses are currently being undertaken to evaluate whether MAE is gene/pathway specific and to understand whether MAE can be employed by cancers to achieve a more aggressive phenotype.http://link.springer.com/article/10.1186/s12967-019-1863-xMonoallelic expressionMelanomaRNA-seq |
| spellingShingle | Lee Silcock Hakeem Almabrazi Younes Mokrab Puthen Jithesh Muna Al-Hashmi Nicola James Rebecca Mathew Valentina Mattei Davide Bedognetti Francesca Lessi Ramzi Temanni Barbara Seliger Rashid Al-Ali Francesco M. Marincola Ena Wang Sara Tomei Monoallelic expression in melanoma Journal of Translational Medicine Monoallelic expression Melanoma RNA-seq |
| title | Monoallelic expression in melanoma |
| title_full | Monoallelic expression in melanoma |
| title_fullStr | Monoallelic expression in melanoma |
| title_full_unstemmed | Monoallelic expression in melanoma |
| title_short | Monoallelic expression in melanoma |
| title_sort | monoallelic expression in melanoma |
| topic | Monoallelic expression Melanoma RNA-seq |
| url | http://link.springer.com/article/10.1186/s12967-019-1863-x |
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