HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages
| Autor: | Thomas Graf, Bruna Barneda-Zahonero, Luisa I. De Andres, Haleh Rafati, Maribel Parra, Olga Collazo, Tokameh Mahmoudi, Abul B. M. M. K. Islam, Nuria Lopez-Bigas, Lars H. Bussmann, Alessandro di Tullio, Lidia Román-González |
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| Přispěvatelé: | Biochemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
lcsh:QH426-470 Macròfags Cellular differentiation Cèl·lules B Immunology Repressor Down-Regulation MADS Domain Proteins Biology Histone Deacetylases 03 medical and health sciences 0302 clinical medicine Genetics Gene silencing Humans Cell Lineage Myeloid Cells Promoter Regions Genetic Molecular Biology Transcription factor Genetics (clinical) Ecology Evolution Behavior and Systematics 030304 developmental biology 0303 health sciences B cells B-Lymphocytes Binding Sites Cèl·lules de la medul·la òssia MEF2 Transcription Factors Lymphopoiesis Macrophages Precursor Cells B-Lymphoid Transdifferentiation HDAC7 Promoter Cell Differentiation Genomics Molecular biology Cell biology lcsh:Genetics Myogenic Regulatory Factors 030220 oncology & carcinogenesis Factors de transcripció Cell Transdifferentiation Chromatin immunoprecipitation Research Article |
| Zdroj: | PLoS Genetics PLoS Genetics (print), 9(5). Public Library of Science Recercat. Dipósit de la Recerca de Catalunya instname Dipòsit Digital de la UB Universidad de Barcelona PLoS Genetics, Vol 9, Iss 5, p e1003503 (2013) |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell–specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes. Author Summary Through the hematopoietic system, all the distinct mature blood cell types are generated, thereby constituting one of the best-studied paradigms for cell lineage commitment and differentiation in biology. B lymphocytes are generated through several cell-commitment, lineage-choice, and differentiation processes. To date, the central role of lineage-specific transcription factors in positively regulating these distinct developmental steps is well established. However, in the absence of proper transcriptional repression, an “adolescent cell” will never be able to reach its “adulthood identity,” having a potential impact in the development of hematological malignancies. In this article, we examined the molecular mechanism responsible for the gene silencing of lineage undesirable genes in B cell precursors and uncovered the role played in this process by the histone deacetylase HDAC7. We show that HDAC7 is expressed in B cell precursors where it interacts with the transcription factor MEF2C and is recruited to the promoters of non-B cell genes. While HDAC7 is down-regulated during the lineage conversion of pre-B cells into macrophages, re-expression of HDAC7 interferes with both the acquisition of the myeloid gene transcriptional program and macrophage-specific cell functions. We therefore have identified a novel lineage-specific transcriptional repressor in the hematopoietic system. |
| Databáze: | OpenAIRE |
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