DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer
<h3>Background</h3><p dir="ltr">Colorectal cancer (CRC) is the third most commonly diagnosed human malignancy worldwide. Upregulation of inhibitory immune checkpoints by tumor-infiltrating immune cells (TIICs) or their ligands by tumor cells leads to tumor evasion from ho...
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| مؤلفون آخرون: | , , , |
| منشور في: |
2018
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| _version_ | 1864513513538453504 |
|---|---|
| author | Varun Sasidharan Nair (5396393) |
| author2 | Salman M. Toor (8854751) Rowaida Z. Taha (8854754) Hibah Shaath (5599658) Eyad Elkord (5396390) |
| author2_role | author author author author |
| author_facet | Varun Sasidharan Nair (5396393) Salman M. Toor (8854751) Rowaida Z. Taha (8854754) Hibah Shaath (5599658) Eyad Elkord (5396390) |
| author_role | author |
| dc.creator.none.fl_str_mv | Varun Sasidharan Nair (5396393) Salman M. Toor (8854751) Rowaida Z. Taha (8854754) Hibah Shaath (5599658) Eyad Elkord (5396390) |
| dc.date.none.fl_str_mv | 2018-08-06T18:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s13148-018-0539-3 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/DNA_methylation_and_repressive_histones_in_the_promoters_of_PD-1_CTLA-4_TIM-3_LAG-3_TIGIT_PD-L1_and_galectin-9_genes_in_human_colorectal_cancer/25920100 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Immunology Oncology and carcinogenesis Colorectal cancer Immune checkpoints PD-L1 Galectin-9 DNA methylation Histone trimethylation |
| dc.title.none.fl_str_mv | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">Colorectal cancer (CRC) is the third most commonly diagnosed human malignancy worldwide. Upregulation of inhibitory immune checkpoints by tumor-infiltrating immune cells (TIICs) or their ligands by tumor cells leads to tumor evasion from host immunosurveillance. Changes in DNA methylation pattern and enrichment of methylated histone marks in the promoter regions could be major contributors to the upregulation of immune checkpoints (ICs) in the tumor microenvironment (TME).</p><h3>Methods</h3><p dir="ltr">Relative expressions of various immune checkpoints and ligands in colon normal tissues (NT) and colorectal tumor tissues (TT) were assessed by qRT-PCR. The epigenetic modifications behind this upregulation were determined by investigating the CpG methylation status of their promoter regions using bisulfite sequencing. Distributions of histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) in promoter regions of these genes were assessed by chromatin immunoprecipitation (ChIP) assay.</p><h3>Results</h3><p dir="ltr">We found that the expression levels of PD-1, CTLA-4, TIM-3, TIGIT, PD-L1, and galectin-9 were significantly higher in colorectal tumor tissues, compared with colon normal tissues. To study the role of DNA methylation, we checked the promoter CpG methylation of ICs and ligands and found that only CTLA-4 and TIGIT, among other genes, were significantly hypomethylated in TT compared with NT. Next, we checked the abundance of repressive histones (H3K9me3 and H3K27me3) in the promoter regions of ICs/ligands. We found that bindings of H3K9me3 in PD-1 and TIGIT promoters and H3K27me3 in CTLA-4 promotor were significantly lower in TT compared with NT. Additionally, bindings of both H3K9me3 and H3K27me3 in the TIM-3 promoter were significantly lower in TT compared with NT.</p><h3>Conclusion</h3><p dir="ltr">This study shows that both DNA hypomethylation and H3K9me3 and H3K27me3 repressive histones are involved in upregulation of CTLA-4 and TIGIT genes. However, repressive histones, but not DNA hypomethylation, are involved in upregulation of PD-1 and TIM-3 genes in CRC tumor tissue. These epigenetic modifications could be utilized as diagnostic biomarkers for CRC.</p><h2>Other Information</h2><p dir="ltr">Published in: Clinical Epigenetics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13148-018-0539-3" target="_blank">https://dx.doi.org/10.1186/s13148-018-0539-3</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_79fc436dd2ac26e9f47f01c557bee586 |
| identifier_str_mv | 10.1186/s13148-018-0539-3 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25920100 |
| publishDate | 2018 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancerVarun Sasidharan Nair (5396393)Salman M. Toor (8854751)Rowaida Z. Taha (8854754)Hibah Shaath (5599658)Eyad Elkord (5396390)Biomedical and clinical sciencesImmunologyOncology and carcinogenesisColorectal cancerImmune checkpointsPD-L1Galectin-9DNA methylationHistone trimethylation<h3>Background</h3><p dir="ltr">Colorectal cancer (CRC) is the third most commonly diagnosed human malignancy worldwide. Upregulation of inhibitory immune checkpoints by tumor-infiltrating immune cells (TIICs) or their ligands by tumor cells leads to tumor evasion from host immunosurveillance. Changes in DNA methylation pattern and enrichment of methylated histone marks in the promoter regions could be major contributors to the upregulation of immune checkpoints (ICs) in the tumor microenvironment (TME).</p><h3>Methods</h3><p dir="ltr">Relative expressions of various immune checkpoints and ligands in colon normal tissues (NT) and colorectal tumor tissues (TT) were assessed by qRT-PCR. The epigenetic modifications behind this upregulation were determined by investigating the CpG methylation status of their promoter regions using bisulfite sequencing. Distributions of histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) in promoter regions of these genes were assessed by chromatin immunoprecipitation (ChIP) assay.</p><h3>Results</h3><p dir="ltr">We found that the expression levels of PD-1, CTLA-4, TIM-3, TIGIT, PD-L1, and galectin-9 were significantly higher in colorectal tumor tissues, compared with colon normal tissues. To study the role of DNA methylation, we checked the promoter CpG methylation of ICs and ligands and found that only CTLA-4 and TIGIT, among other genes, were significantly hypomethylated in TT compared with NT. Next, we checked the abundance of repressive histones (H3K9me3 and H3K27me3) in the promoter regions of ICs/ligands. We found that bindings of H3K9me3 in PD-1 and TIGIT promoters and H3K27me3 in CTLA-4 promotor were significantly lower in TT compared with NT. Additionally, bindings of both H3K9me3 and H3K27me3 in the TIM-3 promoter were significantly lower in TT compared with NT.</p><h3>Conclusion</h3><p dir="ltr">This study shows that both DNA hypomethylation and H3K9me3 and H3K27me3 repressive histones are involved in upregulation of CTLA-4 and TIGIT genes. However, repressive histones, but not DNA hypomethylation, are involved in upregulation of PD-1 and TIM-3 genes in CRC tumor tissue. These epigenetic modifications could be utilized as diagnostic biomarkers for CRC.</p><h2>Other Information</h2><p dir="ltr">Published in: Clinical Epigenetics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13148-018-0539-3" target="_blank">https://dx.doi.org/10.1186/s13148-018-0539-3</a></p>2018-08-06T18:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s13148-018-0539-3https://figshare.com/articles/journal_contribution/DNA_methylation_and_repressive_histones_in_the_promoters_of_PD-1_CTLA-4_TIM-3_LAG-3_TIGIT_PD-L1_and_galectin-9_genes_in_human_colorectal_cancer/25920100CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/259201002018-08-06T18:00:00Z |
| spellingShingle | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer Varun Sasidharan Nair (5396393) Biomedical and clinical sciences Immunology Oncology and carcinogenesis Colorectal cancer Immune checkpoints PD-L1 Galectin-9 DNA methylation Histone trimethylation |
| status_str | publishedVersion |
| title | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer |
| title_full | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer |
| title_fullStr | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer |
| title_full_unstemmed | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer |
| title_short | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer |
| title_sort | DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer |
| topic | Biomedical and clinical sciences Immunology Oncology and carcinogenesis Colorectal cancer Immune checkpoints PD-L1 Galectin-9 DNA methylation Histone trimethylation |