A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis
The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouse Kdm1a deletion causes a dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3...
| Main Authors: | , , , , , |
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| Format: | Article |
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eLife Sciences Publications Ltd
2024-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/86168 |
| _version_ | 1797292447698518016 |
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| author | Pengfei Guo Rebecca C Lim Keshari Rajawasam Tiffany Trinh Hong Sun Hui Zhang |
| author_facet | Pengfei Guo Rebecca C Lim Keshari Rajawasam Tiffany Trinh Hong Sun Hui Zhang |
| author_sort | Pengfei Guo |
| collection | DOAJ |
| description | The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouse Kdm1a deletion causes a dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3mbtl3 or Dcaf5 results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4DCAF5 ubiquitin ligase. KDM1A (LSD1) demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse Ezh2K20R/K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and Ezh2K20R/K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation-dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to regulate the PRC2 activity and hematopoiesis. |
| first_indexed | 2024-03-07T19:52:42Z |
| format | Article |
| id | doaj.art-e8f7d98cce8846728005edba7f2a38be |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-07T19:52:42Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-e8f7d98cce8846728005edba7f2a38be2024-02-28T15:13:08ZengeLife Sciences Publications LtdeLife2050-084X2024-02-011310.7554/eLife.86168A methylation-phosphorylation switch controls EZH2 stability and hematopoiesisPengfei Guo0https://orcid.org/0000-0001-6734-6549Rebecca C Lim1Keshari Rajawasam2Tiffany Trinh3Hong Sun4Hui Zhang5https://orcid.org/0000-0001-6028-2554Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, United StatesDepartment of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, United StatesDepartment of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, United StatesDepartment of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, United StatesDepartment of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, United StatesDepartment of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, United StatesThe Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouse Kdm1a deletion causes a dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3mbtl3 or Dcaf5 results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4DCAF5 ubiquitin ligase. KDM1A (LSD1) demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse Ezh2K20R/K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and Ezh2K20R/K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation-dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to regulate the PRC2 activity and hematopoiesis.https://elifesciences.org/articles/86168EZH2PRC2L3MBTL3SET7DCAF5KDM1A |
| spellingShingle | Pengfei Guo Rebecca C Lim Keshari Rajawasam Tiffany Trinh Hong Sun Hui Zhang A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis eLife EZH2 PRC2 L3MBTL3 SET7 DCAF5 KDM1A |
| title | A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis |
| title_full | A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis |
| title_fullStr | A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis |
| title_full_unstemmed | A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis |
| title_short | A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis |
| title_sort | methylation phosphorylation switch controls ezh2 stability and hematopoiesis |
| topic | EZH2 PRC2 L3MBTL3 SET7 DCAF5 KDM1A |
| url | https://elifesciences.org/articles/86168 |
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