Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficiently
Abstract Circulating blood platelets are responsible for maintaining hemostasis. They are released into blood vessels from mature megakaryocytes. Although several transcription factors have been reported to orchestrate the transcriptional programs required for platelet production, how chromatin regu...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61247-6 |
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| author | Guozhen Gao Josimar Dornelas Moreira Prosun Das Kevin Lin Kai Ge Taiping Chen Yue Lu Margarida A. Santos |
| author_facet | Guozhen Gao Josimar Dornelas Moreira Prosun Das Kevin Lin Kai Ge Taiping Chen Yue Lu Margarida A. Santos |
| author_sort | Guozhen Gao |
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| description | Abstract Circulating blood platelets are responsible for maintaining hemostasis. They are released into blood vessels from mature megakaryocytes. Although several transcription factors have been reported to orchestrate the transcriptional programs required for platelet production, how chromatin regulators control these processes is still poorly understood. MLL3 and MLL4 are the main lysine methyltransferases responsible for the deposition of H3K4me1 histone marks at enhancers. MLL3 and MLL4 typically form complexes with other co-factors, such as PTIP. Recently, we showed that loss of PTIP leads to decreased platelet numbers in mice. Here, we find that, although MLL3/4 double deficiency does not alter megakaryopoiesis and endomitosis, the final step of megakaryocyte maturation is affected due to an abnormal cytoskeleton and demarcation membrane system. MLL3/4 double-deficient mice develop macrothrombocytopenia; platelets are preactive and pro-apoptotic, leading to their rapid clearance from the circulation. Increased megakaryopoeisis in the bone marrow and spleen cannot compensate for these abnormalities. Mechanistically, the expression of genes responsible for normal megakaryocyte function and platelet production is altered in MLL3/4-deficient megakaryocytes, partly due to impaired enhancer functions associated with these genes. Our findings provide insights into the epigenetic programs that are important for platelet biogenesis. |
| format | Article |
| id | doaj-art-7d8816ca738e4a24a0cfdf4d9116a9fa |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-7d8816ca738e4a24a0cfdf4d9116a9fa2025-08-20T03:37:37ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-61247-6Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficientlyGuozhen Gao0Josimar Dornelas Moreira1Prosun Das2Kevin Lin3Kai Ge4Taiping Chen5Yue Lu6Margarida A. Santos7Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Biochemistry, Sapthagiri Institute of Medical Sciences & Research Centre, Sapthagiri NPS UniversityDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterNational Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterAbstract Circulating blood platelets are responsible for maintaining hemostasis. They are released into blood vessels from mature megakaryocytes. Although several transcription factors have been reported to orchestrate the transcriptional programs required for platelet production, how chromatin regulators control these processes is still poorly understood. MLL3 and MLL4 are the main lysine methyltransferases responsible for the deposition of H3K4me1 histone marks at enhancers. MLL3 and MLL4 typically form complexes with other co-factors, such as PTIP. Recently, we showed that loss of PTIP leads to decreased platelet numbers in mice. Here, we find that, although MLL3/4 double deficiency does not alter megakaryopoiesis and endomitosis, the final step of megakaryocyte maturation is affected due to an abnormal cytoskeleton and demarcation membrane system. MLL3/4 double-deficient mice develop macrothrombocytopenia; platelets are preactive and pro-apoptotic, leading to their rapid clearance from the circulation. Increased megakaryopoeisis in the bone marrow and spleen cannot compensate for these abnormalities. Mechanistically, the expression of genes responsible for normal megakaryocyte function and platelet production is altered in MLL3/4-deficient megakaryocytes, partly due to impaired enhancer functions associated with these genes. Our findings provide insights into the epigenetic programs that are important for platelet biogenesis.https://doi.org/10.1038/s41467-025-61247-6 |
| spellingShingle | Guozhen Gao Josimar Dornelas Moreira Prosun Das Kevin Lin Kai Ge Taiping Chen Yue Lu Margarida A. Santos Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficiently Nature Communications |
| title | Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficiently |
| title_full | Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficiently |
| title_fullStr | Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficiently |
| title_full_unstemmed | Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficiently |
| title_short | Histone lysine methyltransferases MLL3 and MLL4 direct gene expression to produce platelets efficiently |
| title_sort | histone lysine methyltransferases mll3 and mll4 direct gene expression to produce platelets efficiently |
| url | https://doi.org/10.1038/s41467-025-61247-6 |
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