An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes
Liver regeneration is characterized by cell cycle reentrance of hepatocytes. N-Myc, encoded by MYCN, is a member of the Myc family of transcription factors. Elevation of MYCN expression has been noted in the course of liver regeneration whereas the underlying mechanism remains unclear. Here we descr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.742319/full |
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| author | Zhiwen Fan Zhiwen Fan Ming Kong Xiulian Miao Yan Guo Haozhen Ren Haozhen Ren Jinglin Wang Jinglin Wang Shuai Wang Shuai Wang Ning Tang Ning Tang Longcheng Shang Zhengyi Zhu Hanyi Liu Wei Zhu Xiaolei Shi Xiaolei Shi |
| author_facet | Zhiwen Fan Zhiwen Fan Ming Kong Xiulian Miao Yan Guo Haozhen Ren Haozhen Ren Jinglin Wang Jinglin Wang Shuai Wang Shuai Wang Ning Tang Ning Tang Longcheng Shang Zhengyi Zhu Hanyi Liu Wei Zhu Xiaolei Shi Xiaolei Shi |
| author_sort | Zhiwen Fan |
| collection | DOAJ |
| description | Liver regeneration is characterized by cell cycle reentrance of hepatocytes. N-Myc, encoded by MYCN, is a member of the Myc family of transcription factors. Elevation of MYCN expression has been noted in the course of liver regeneration whereas the underlying mechanism remains unclear. Here we describe that up-regulation of MYCN expression, as measured by quantitative PCR, Western blotting, and immunohistochemical staining, paralleled liver regeneration in animal and cell models. MYCN expression was up-regulated as a result of transcriptional activation. Ingenuity pathway analysis (IPA) revealed several up-stream transcriptional regulators for MYCN and RNA interference validated E2F5 and TFDP1 as essential for hepatocyte growth factor (HGF)-induced MYCN trans-activation. Further examination showed that deficiency of BRG1, a chromatin remodeling protein, attenuated MYCN induction during liver regeneration. BRG1 interacted with and was recruited by E2F5/TFDP1 to the MYCN promoter. Mechanistically, BRG1 might play a role regulating histone H3 acetylation and H3K4 trimethylation and facilitating/stabilizing the binding of RNA polymerase II surrounding the MYCN promoter. Over-expression of ectopic MYCN in BRG1-null hepatocytes overcame deficiency of proliferation. Importantly, a positive correlation between MYCN expression and BRG1/E2F5/TFDP1 expression was observed in human liver specimens. In conclusion, our data identify a novel epigenetic pathway where an E2F5-TFDP1-BRG1 complex regulates MYCN transcription to promote liver regeneration. |
| first_indexed | 2024-12-21T08:26:36Z |
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| id | doaj.art-91726273fed8495f8e617560a2bdf3dc |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-21T08:26:36Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-91726273fed8495f8e617560a2bdf3dc2022-12-21T19:10:19ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-10-01910.3389/fcell.2021.742319742319An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in HepatocytesZhiwen Fan0Zhiwen Fan1Ming Kong2Xiulian Miao3Yan Guo4Haozhen Ren5Haozhen Ren6Jinglin Wang7Jinglin Wang8Shuai Wang9Shuai Wang10Ning Tang11Ning Tang12Longcheng Shang13Zhengyi Zhu14Hanyi Liu15Wei Zhu16Xiaolei Shi17Xiaolei Shi18Department of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaHepatobiliary Institute, Nanjing University, Nanjing, ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, and Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaCollege of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, ChinaCollege of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaHepatobiliary Institute, Nanjing University, Nanjing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaHepatobiliary Institute, Nanjing University, Nanjing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaHepatobiliary Institute, Nanjing University, Nanjing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaHepatobiliary Institute, Nanjing University, Nanjing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaDepartment of Anesthesiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaHepatobiliary Institute, Nanjing University, Nanjing, ChinaLiver regeneration is characterized by cell cycle reentrance of hepatocytes. N-Myc, encoded by MYCN, is a member of the Myc family of transcription factors. Elevation of MYCN expression has been noted in the course of liver regeneration whereas the underlying mechanism remains unclear. Here we describe that up-regulation of MYCN expression, as measured by quantitative PCR, Western blotting, and immunohistochemical staining, paralleled liver regeneration in animal and cell models. MYCN expression was up-regulated as a result of transcriptional activation. Ingenuity pathway analysis (IPA) revealed several up-stream transcriptional regulators for MYCN and RNA interference validated E2F5 and TFDP1 as essential for hepatocyte growth factor (HGF)-induced MYCN trans-activation. Further examination showed that deficiency of BRG1, a chromatin remodeling protein, attenuated MYCN induction during liver regeneration. BRG1 interacted with and was recruited by E2F5/TFDP1 to the MYCN promoter. Mechanistically, BRG1 might play a role regulating histone H3 acetylation and H3K4 trimethylation and facilitating/stabilizing the binding of RNA polymerase II surrounding the MYCN promoter. Over-expression of ectopic MYCN in BRG1-null hepatocytes overcame deficiency of proliferation. Importantly, a positive correlation between MYCN expression and BRG1/E2F5/TFDP1 expression was observed in human liver specimens. In conclusion, our data identify a novel epigenetic pathway where an E2F5-TFDP1-BRG1 complex regulates MYCN transcription to promote liver regeneration.https://www.frontiersin.org/articles/10.3389/fcell.2021.742319/fulltranscriptional regulationhepatocyteliver regenerationepigeneticschromatin remodeling proteinproliferation |
| spellingShingle | Zhiwen Fan Zhiwen Fan Ming Kong Xiulian Miao Yan Guo Haozhen Ren Haozhen Ren Jinglin Wang Jinglin Wang Shuai Wang Shuai Wang Ning Tang Ning Tang Longcheng Shang Zhengyi Zhu Hanyi Liu Wei Zhu Xiaolei Shi Xiaolei Shi An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes Frontiers in Cell and Developmental Biology transcriptional regulation hepatocyte liver regeneration epigenetics chromatin remodeling protein proliferation |
| title | An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes |
| title_full | An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes |
| title_fullStr | An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes |
| title_full_unstemmed | An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes |
| title_short | An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes |
| title_sort | e2f5 tfdp1 brg1 complex mediates transcriptional activation of mycn in hepatocytes |
| topic | transcriptional regulation hepatocyte liver regeneration epigenetics chromatin remodeling protein proliferation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.742319/full |
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