FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome
Wiskott–Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the WAS gene, which together with its homolog, N-WASP, regulates actin cytoskeleton remodeling and cell motility. WAS patients suffer from microthrombocytopenia, characterized by a diminished num...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.607836/full |
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| author | Chunlin Wang Chunlin Wang Klarke M. Sample Babu Gajendran Babu Gajendran Philipp Kapranov Wuling Liu Wuling Liu Anling Hu Anling Hu Eldad Zacksenhaus Eldad Zacksenhaus Yanmei Li Yanmei Li Xiaojiang Hao Xiaojiang Hao Yaacov Ben-David Yaacov Ben-David |
| author_facet | Chunlin Wang Chunlin Wang Klarke M. Sample Babu Gajendran Babu Gajendran Philipp Kapranov Wuling Liu Wuling Liu Anling Hu Anling Hu Eldad Zacksenhaus Eldad Zacksenhaus Yanmei Li Yanmei Li Xiaojiang Hao Xiaojiang Hao Yaacov Ben-David Yaacov Ben-David |
| author_sort | Chunlin Wang |
| collection | DOAJ |
| description | Wiskott–Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the WAS gene, which together with its homolog, N-WASP, regulates actin cytoskeleton remodeling and cell motility. WAS patients suffer from microthrombocytopenia, characterized by a diminished number and size of platelets, though the underlying mechanism is not fully understood. Here, we identified FLI1 as a direct transcriptional regulator of WAS and its binding partner WIP. Depletion of either WAS or WIP in human erythroleukemic cells accelerated cell proliferation, suggesting tumor suppressor function of both genes in leukemia. Depletion of WAS/WIP also led to a significant reduction in the percentage of CD41 and CD61 positive cells, which mark committed megakaryocytes. RNAseq analysis revealed common changes in megakaryocytic gene expression following FLI1 or WASP knockdown. However, in contrast to FLI1, WASP depletion did not alter expression of late-stage platelet-inducing genes. N-WASP was not regulated by FLI1, yet its silencing also reduced the percentage of CD41+ and CD61+ megakaryocytes. Moreover, combined knockdown of WASP and N-WASP further suppressed megakaryocyte differentiation, indicating a major cooperation of these related genes in controlling megakaryocytic cell fate. However, unlike WASP/WIP, N-WASP loss suppressed leukemic cell proliferation. WASP, WIP and N-WASP depletion led to induction of FLI1 expression, mediated by GATA1, and this may mitigate the severity of platelet deficiency in WAS patients. Together, these results uncover a crucial role for FLI1 in megakaryocyte differentiation, implicating this transcription factor in regulating microthrombocytopenia associated with Wiskott–Aldrich syndrome. |
| first_indexed | 2024-12-20T02:51:37Z |
| format | Article |
| id | doaj.art-a925b2552a9c471eb1e7e8e64a1d2c17 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T02:51:37Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a925b2552a9c471eb1e7e8e64a1d2c172022-12-21T19:56:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.607836607836FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich SyndromeChunlin Wang0Chunlin Wang1Klarke M. Sample2Babu Gajendran3Babu Gajendran4Philipp Kapranov5Wuling Liu6Wuling Liu7Anling Hu8Anling Hu9Eldad Zacksenhaus10Eldad Zacksenhaus11Yanmei Li12Yanmei Li13Xiaojiang Hao14Xiaojiang Hao15Yaacov Ben-David16Yaacov Ben-David17State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, ChinaThe Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, ChinaThe National Health Commission’s Key Laboratory of Immunological Pulmonary Disease, Guizhou Provincial People’s Hospital, The Affiliated Hospital of Guizhou University, Guiyang, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, ChinaThe Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, ChinaSchool of Biomedical Sciences, Institute of Genomics, Huaqiao University, Xiamen, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, ChinaThe Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, ChinaThe Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, ChinaDepartment of Medicine, University of Toronto, Toronto, ON, CanadaDivision of Advanced Diagnostics, Toronto General Research Institute—University Health Network, Toronto, ON, CanadaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, ChinaThe Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, ChinaThe Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, ChinaThe Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, ChinaWiskott–Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the WAS gene, which together with its homolog, N-WASP, regulates actin cytoskeleton remodeling and cell motility. WAS patients suffer from microthrombocytopenia, characterized by a diminished number and size of platelets, though the underlying mechanism is not fully understood. Here, we identified FLI1 as a direct transcriptional regulator of WAS and its binding partner WIP. Depletion of either WAS or WIP in human erythroleukemic cells accelerated cell proliferation, suggesting tumor suppressor function of both genes in leukemia. Depletion of WAS/WIP also led to a significant reduction in the percentage of CD41 and CD61 positive cells, which mark committed megakaryocytes. RNAseq analysis revealed common changes in megakaryocytic gene expression following FLI1 or WASP knockdown. However, in contrast to FLI1, WASP depletion did not alter expression of late-stage platelet-inducing genes. N-WASP was not regulated by FLI1, yet its silencing also reduced the percentage of CD41+ and CD61+ megakaryocytes. Moreover, combined knockdown of WASP and N-WASP further suppressed megakaryocyte differentiation, indicating a major cooperation of these related genes in controlling megakaryocytic cell fate. However, unlike WASP/WIP, N-WASP loss suppressed leukemic cell proliferation. WASP, WIP and N-WASP depletion led to induction of FLI1 expression, mediated by GATA1, and this may mitigate the severity of platelet deficiency in WAS patients. Together, these results uncover a crucial role for FLI1 in megakaryocyte differentiation, implicating this transcription factor in regulating microthrombocytopenia associated with Wiskott–Aldrich syndrome.https://www.frontiersin.org/articles/10.3389/fimmu.2021.607836/fullWiskott–Aldrich SyndromemegakaryopoiesismicrothrombocytopeniaFLI1immunodeficiencyWASP |
| spellingShingle | Chunlin Wang Chunlin Wang Klarke M. Sample Babu Gajendran Babu Gajendran Philipp Kapranov Wuling Liu Wuling Liu Anling Hu Anling Hu Eldad Zacksenhaus Eldad Zacksenhaus Yanmei Li Yanmei Li Xiaojiang Hao Xiaojiang Hao Yaacov Ben-David Yaacov Ben-David FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome Frontiers in Immunology Wiskott–Aldrich Syndrome megakaryopoiesis microthrombocytopenia FLI1 immunodeficiency WASP |
| title | FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome |
| title_full | FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome |
| title_fullStr | FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome |
| title_full_unstemmed | FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome |
| title_short | FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome |
| title_sort | fli1 induces megakaryopoiesis gene expression through was wip dependent and independent mechanisms implications for wiskott aldrich syndrome |
| topic | Wiskott–Aldrich Syndrome megakaryopoiesis microthrombocytopenia FLI1 immunodeficiency WASP |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.607836/full |
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