3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma
Abstract The fundamental cause of transcription dysregulation in hepatocellular carcinoma (HCC) remains elusive. To investigate the underlying mechanisms, comprehensive 3D‐epigenomic analyses are performed in cellular models of THLE2 (a normal hepatocytes cell line) and HepG2 (a hepatocellular carci...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-12-01
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| Series: | Advanced Genetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ggn2.202100010 |
| _version_ | 1828088729407848448 |
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| author | Yuliang Feng Ping Wang Liuyang Cai Meixiao Zhan Fan He Jiahui Wang Yong Li Eva Gega Wei Zhang Wei Zhao Yongjie Xin Xudong Chen Yijun Ruan Ligong Lu |
| author_facet | Yuliang Feng Ping Wang Liuyang Cai Meixiao Zhan Fan He Jiahui Wang Yong Li Eva Gega Wei Zhang Wei Zhao Yongjie Xin Xudong Chen Yijun Ruan Ligong Lu |
| author_sort | Yuliang Feng |
| collection | DOAJ |
| description | Abstract The fundamental cause of transcription dysregulation in hepatocellular carcinoma (HCC) remains elusive. To investigate the underlying mechanisms, comprehensive 3D‐epigenomic analyses are performed in cellular models of THLE2 (a normal hepatocytes cell line) and HepG2 (a hepatocellular carcinoma cell line) using integrative approaches for chromatin topology, genomic and epigenomic variation, and transcriptional output. Comparing the 3D‐epigenomes in THLE2 and HepG2 reveal that most HCC‐associated genes are organized in complex chromatin interactions mediated by RNA polymerase II (RNAPII). Incorporation of genome‐wide association studies (GWAS) data enables the identification of non‐coding genetic variants that are enriched in distal enhancers connecting to the promoters of HCC‐associated genes via long‐range chromatin interactions, highlighting their functional roles. Interestingly, CTCF binding and looping proximal to HCC‐associated genes appear to form chromatin architectures that overarch RNAPII‐mediated chromatin interactions. It is further demonstrated that epigenetic variants by DNA hypomethylation at a subset of CTCF motifs proximal to HCC‐associated genes can modify chromatin topological configuration, which in turn alter RNAPII‐mediated chromatin interactions and lead to dysregulation of transcription. Together, the 3D‐epigenomic analyses provide novel insights of multifaceted interplays involving genetics, epigenetics, and chromatin topology in HCC cells. |
| first_indexed | 2024-04-11T05:30:57Z |
| format | Article |
| id | doaj.art-e8916d36ad80468a98fa4577d6ea5c4e |
| institution | Directory Open Access Journal |
| issn | 2641-6573 |
| language | English |
| last_indexed | 2024-04-11T05:30:57Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Genetics |
| spelling | doaj.art-e8916d36ad80468a98fa4577d6ea5c4e2022-12-23T02:32:11ZengWileyAdvanced Genetics2641-65732022-12-0134n/an/a10.1002/ggn2.2021000103D‐Epigenomic Regulation of Gene Transcription in Hepatocellular CarcinomaYuliang Feng0Ping Wang1Liuyang Cai2Meixiao Zhan3Fan He4Jiahui Wang5Yong Li6Eva Gega7Wei Zhang8Wei Zhao9Yongjie Xin10Xudong Chen11Yijun Ruan12Ligong Lu13Zhuhai Precision Medical Center Zhuhai People's Hospital Zhuhai Hospital Affiliated with Jinan University Zhuhai Guangdong 519000 P. R. ChinaThe Jackson Laboratory for Genomic Medicine Farmington CT 06032 USAThe Jackson Laboratory for Genomic Medicine Farmington CT 06032 USAZhuhai Precision Medical Center Zhuhai People's Hospital Zhuhai Hospital Affiliated with Jinan University Zhuhai Guangdong 519000 P. R. ChinaDepartment of Interventional Radiology Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology) Shenzhen Guangdong 518020 P. R. ChinaThe Jackson Laboratory for Genomic Medicine Farmington CT 06032 USAZhuhai Precision Medical Center Zhuhai People's Hospital Zhuhai Hospital Affiliated with Jinan University Zhuhai Guangdong 519000 P. R. ChinaThe Jackson Laboratory for Genomic Medicine Farmington CT 06032 USADepartment of Interventional Radiology Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology) Shenzhen Guangdong 518020 P. R. ChinaZhuhai Precision Medical Center Zhuhai People's Hospital Zhuhai Hospital Affiliated with Jinan University Zhuhai Guangdong 519000 P. R. ChinaZhuhai Precision Medical Center Zhuhai People's Hospital Zhuhai Hospital Affiliated with Jinan University Zhuhai Guangdong 519000 P. R. ChinaDepartment of Interventional Radiology Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology) Shenzhen Guangdong 518020 P. R. ChinaThe Jackson Laboratory for Genomic Medicine Farmington CT 06032 USAZhuhai Precision Medical Center Zhuhai People's Hospital Zhuhai Hospital Affiliated with Jinan University Zhuhai Guangdong 519000 P. R. ChinaAbstract The fundamental cause of transcription dysregulation in hepatocellular carcinoma (HCC) remains elusive. To investigate the underlying mechanisms, comprehensive 3D‐epigenomic analyses are performed in cellular models of THLE2 (a normal hepatocytes cell line) and HepG2 (a hepatocellular carcinoma cell line) using integrative approaches for chromatin topology, genomic and epigenomic variation, and transcriptional output. Comparing the 3D‐epigenomes in THLE2 and HepG2 reveal that most HCC‐associated genes are organized in complex chromatin interactions mediated by RNA polymerase II (RNAPII). Incorporation of genome‐wide association studies (GWAS) data enables the identification of non‐coding genetic variants that are enriched in distal enhancers connecting to the promoters of HCC‐associated genes via long‐range chromatin interactions, highlighting their functional roles. Interestingly, CTCF binding and looping proximal to HCC‐associated genes appear to form chromatin architectures that overarch RNAPII‐mediated chromatin interactions. It is further demonstrated that epigenetic variants by DNA hypomethylation at a subset of CTCF motifs proximal to HCC‐associated genes can modify chromatin topological configuration, which in turn alter RNAPII‐mediated chromatin interactions and lead to dysregulation of transcription. Together, the 3D‐epigenomic analyses provide novel insights of multifaceted interplays involving genetics, epigenetics, and chromatin topology in HCC cells.https://doi.org/10.1002/ggn2.2021000103D genome3D‐epigeomeChIA‐PETchromatin topologyhepatocellular carcinomatranscription regulation |
| spellingShingle | Yuliang Feng Ping Wang Liuyang Cai Meixiao Zhan Fan He Jiahui Wang Yong Li Eva Gega Wei Zhang Wei Zhao Yongjie Xin Xudong Chen Yijun Ruan Ligong Lu 3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma Advanced Genetics 3D genome 3D‐epigeome ChIA‐PET chromatin topology hepatocellular carcinoma transcription regulation |
| title | 3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma |
| title_full | 3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma |
| title_fullStr | 3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma |
| title_full_unstemmed | 3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma |
| title_short | 3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma |
| title_sort | 3d epigenomic regulation of gene transcription in hepatocellular carcinoma |
| topic | 3D genome 3D‐epigeome ChIA‐PET chromatin topology hepatocellular carcinoma transcription regulation |
| url | https://doi.org/10.1002/ggn2.202100010 |
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