MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells
Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elonga...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713001629 |
| _version_ | 1811317205622587392 |
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| author | Emanuel Maethner Maria-Paz Garcia-Cuellar Constanze Breitinger Sylvia Takacova Vladimir Divoky Jay L. Hess Robert K. Slany |
| author_facet | Emanuel Maethner Maria-Paz Garcia-Cuellar Constanze Breitinger Sylvia Takacova Vladimir Divoky Jay L. Hess Robert K. Slany |
| author_sort | Emanuel Maethner |
| collection | DOAJ |
| description | Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay, and this effect was neutralized by direct association with ENL. Correspondingly, CBX8-binding-defective MLL-ENL could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as a neomorphic activity that may augment Polycomb inhibition and transformation. |
| first_indexed | 2024-04-13T12:02:37Z |
| format | Article |
| id | doaj.art-640a9373d2684bb197a168258ccb394f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T12:02:37Z |
| publishDate | 2013-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-640a9373d2684bb197a168258ccb394f2022-12-22T02:47:44ZengElsevierCell Reports2211-12472013-05-01351553156610.1016/j.celrep.2013.03.038MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic CellsEmanuel Maethner0Maria-Paz Garcia-Cuellar1Constanze Breitinger2Sylvia Takacova3Vladimir Divoky4Jay L. Hess5Robert K. Slany6Department of Genetics, University Erlangen, 91058 Erlangen, GermanyDepartment of Genetics, University Erlangen, 91058 Erlangen, GermanyDepartment of Genetics, University Erlangen, 91058 Erlangen, GermanyDepartment of Biology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech RepublicDepartment of Biology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech RepublicDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Genetics, University Erlangen, 91058 Erlangen, GermanyStimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay, and this effect was neutralized by direct association with ENL. Correspondingly, CBX8-binding-defective MLL-ENL could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as a neomorphic activity that may augment Polycomb inhibition and transformation.http://www.sciencedirect.com/science/article/pii/S2211124713001629 |
| spellingShingle | Emanuel Maethner Maria-Paz Garcia-Cuellar Constanze Breitinger Sylvia Takacova Vladimir Divoky Jay L. Hess Robert K. Slany MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells Cell Reports |
| title | MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells |
| title_full | MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells |
| title_fullStr | MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells |
| title_full_unstemmed | MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells |
| title_short | MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells |
| title_sort | mll enl inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713001629 |
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