Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
Summary: Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mec...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-05-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222004667 |
| _version_ | 1817980948527972352 |
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| author | Daisuke Aibara Shogo Takahashi Tomoki Yagai Donghwan Kim Chad N. Brocker Moshe Levi Kimihiko Matsusue Frank J. Gonzalez |
| author_facet | Daisuke Aibara Shogo Takahashi Tomoki Yagai Donghwan Kim Chad N. Brocker Moshe Levi Kimihiko Matsusue Frank J. Gonzalez |
| author_sort | Daisuke Aibara |
| collection | DOAJ |
| description | Summary: Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by which PPARA promotes hepatocyte proliferation in mice. Activation of PPARA by agonist treatment was autoregulated, and induced expression of the epigenetic regulator UHRF1 via activation of the newly described PPARA target gene E2f8, which, in turn, regulates Uhrf1. UHRF1 strongly repressed the expression of CDH1 via methylation of the Cdh1 promoter marked with H3K9me3. Repression of CDH1 by PPARA activation was reversed by PPARA deficiency or knockdown of E2F8 or UHRF1. Furthermore, a forced expression of CDH1 inhibited expression of the Wnt signaling target genes such as Myc after PPARA activation, and suppressed hepatocyte hyperproliferation. These results demonstrate that the PPARA-E2F8-UHRF1-CDH1 axis causes epigenetic regulation of hepatocyte proliferation. |
| first_indexed | 2024-04-13T23:00:33Z |
| format | Article |
| id | doaj.art-3a21a97cbd064185964173dc54e370f8 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-13T23:00:33Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-3a21a97cbd064185964173dc54e370f82022-12-22T02:25:52ZengElsevieriScience2589-00422022-05-01255104196Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferationDaisuke Aibara0Shogo Takahashi1Tomoki Yagai2Donghwan Kim3Chad N. Brocker4Moshe Levi5Kimihiko Matsusue6Frank J. Gonzalez7Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanLaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20057, USA; Corresponding authorLaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USADepartment of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20057, USAFaculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanLaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding authorSummary: Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by which PPARA promotes hepatocyte proliferation in mice. Activation of PPARA by agonist treatment was autoregulated, and induced expression of the epigenetic regulator UHRF1 via activation of the newly described PPARA target gene E2f8, which, in turn, regulates Uhrf1. UHRF1 strongly repressed the expression of CDH1 via methylation of the Cdh1 promoter marked with H3K9me3. Repression of CDH1 by PPARA activation was reversed by PPARA deficiency or knockdown of E2F8 or UHRF1. Furthermore, a forced expression of CDH1 inhibited expression of the Wnt signaling target genes such as Myc after PPARA activation, and suppressed hepatocyte hyperproliferation. These results demonstrate that the PPARA-E2F8-UHRF1-CDH1 axis causes epigenetic regulation of hepatocyte proliferation.http://www.sciencedirect.com/science/article/pii/S2589004222004667Molecular biologyMolecular mechanism of gene regulationTranscriptomics |
| spellingShingle | Daisuke Aibara Shogo Takahashi Tomoki Yagai Donghwan Kim Chad N. Brocker Moshe Levi Kimihiko Matsusue Frank J. Gonzalez Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation iScience Molecular biology Molecular mechanism of gene regulation Transcriptomics |
| title | Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation |
| title_full | Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation |
| title_fullStr | Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation |
| title_full_unstemmed | Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation |
| title_short | Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation |
| title_sort | gene repression through epigenetic modulation by ppara enhances hepatocellular proliferation |
| topic | Molecular biology Molecular mechanism of gene regulation Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222004667 |
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