Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications
Abstract Background DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiati...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-05-01
|
| Series: | BMC Genomics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12864-023-09341-1 |
| _version_ | 1797832236328812544 |
|---|---|
| author | Yang Lu Qiang Cao Yue Yu Yazhou Sun Xuan Jiang Xin Li |
| author_facet | Yang Lu Qiang Cao Yue Yu Yazhou Sun Xuan Jiang Xin Li |
| author_sort | Yang Lu |
| collection | DOAJ |
| description | Abstract Background DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. Results Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn’t change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. Conclusion In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies. |
| first_indexed | 2024-04-09T14:04:35Z |
| format | Article |
| id | doaj.art-947060ed4e7c4b5db9756d7d7d10fdf4 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-04-09T14:04:35Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-947060ed4e7c4b5db9756d7d7d10fdf42023-05-07T11:06:26ZengBMCBMC Genomics1471-21642023-05-0124111910.1186/s12864-023-09341-1Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modificationsYang Lu0Qiang Cao1Yue Yu2Yazhou Sun3Xuan Jiang4Xin Li5School of Medicine, Shenzhen Campus of Sun Yat-Sen UniversitySchool of Medicine, Shenzhen Campus of Sun Yat-Sen UniversitySchool of Medicine, Shenzhen Campus of Sun Yat-Sen UniversityThe Seventh Affiliated Hospital of Sun Yat-Sen UniversitySchool of Medicine, Shenzhen Campus of Sun Yat-Sen UniversitySchool of Medicine, Shenzhen Campus of Sun Yat-Sen UniversityAbstract Background DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. Results Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn’t change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. Conclusion In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies.https://doi.org/10.1186/s12864-023-09341-1CancerPromoter CGIsDNA methylationH3K4me1LSD1Bivalent promoters |
| spellingShingle | Yang Lu Qiang Cao Yue Yu Yazhou Sun Xuan Jiang Xin Li Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications BMC Genomics Cancer Promoter CGIs DNA methylation H3K4me1 LSD1 Bivalent promoters |
| title | Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications |
| title_full | Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications |
| title_fullStr | Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications |
| title_full_unstemmed | Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications |
| title_short | Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications |
| title_sort | pan cancer analysis revealed h3k4me1 at bivalent promoters premarks dna hypermethylation during tumor development and identified the regulatory role of dna methylation in relation to histone modifications |
| topic | Cancer Promoter CGIs DNA methylation H3K4me1 LSD1 Bivalent promoters |
| url | https://doi.org/10.1186/s12864-023-09341-1 |
| work_keys_str_mv | AT yanglu pancanceranalysisrevealedh3k4me1atbivalentpromoterspremarksdnahypermethylationduringtumordevelopmentandidentifiedtheregulatoryroleofdnamethylationinrelationtohistonemodifications AT qiangcao pancanceranalysisrevealedh3k4me1atbivalentpromoterspremarksdnahypermethylationduringtumordevelopmentandidentifiedtheregulatoryroleofdnamethylationinrelationtohistonemodifications AT yueyu pancanceranalysisrevealedh3k4me1atbivalentpromoterspremarksdnahypermethylationduringtumordevelopmentandidentifiedtheregulatoryroleofdnamethylationinrelationtohistonemodifications AT yazhousun pancanceranalysisrevealedh3k4me1atbivalentpromoterspremarksdnahypermethylationduringtumordevelopmentandidentifiedtheregulatoryroleofdnamethylationinrelationtohistonemodifications AT xuanjiang pancanceranalysisrevealedh3k4me1atbivalentpromoterspremarksdnahypermethylationduringtumordevelopmentandidentifiedtheregulatoryroleofdnamethylationinrelationtohistonemodifications AT xinli pancanceranalysisrevealedh3k4me1atbivalentpromoterspremarksdnahypermethylationduringtumordevelopmentandidentifiedtheregulatoryroleofdnamethylationinrelationtohistonemodifications |