Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs
Abstract Background Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription fa...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | BMC Biology |
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| Online Access: | https://doi.org/10.1186/s12915-022-01315-1 |
| _version_ | 1811235401113796608 |
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| author | A. Lorzadeh C. Hammond F. Wang D. J. H. F. Knapp J. CH. Wong J. Y. A. Zhu Q. Cao A. Heravi-Moussavi A. Carles M. Wong Z. Sharafian J. Steif M. Moksa M. Bilenky P. M. Lavoie C. J. Eaves M. Hirst |
| author_facet | A. Lorzadeh C. Hammond F. Wang D. J. H. F. Knapp J. CH. Wong J. Y. A. Zhu Q. Cao A. Heravi-Moussavi A. Carles M. Wong Z. Sharafian J. Steif M. Moksa M. Bilenky P. M. Lavoie C. J. Eaves M. Hirst |
| author_sort | A. Lorzadeh |
| collection | DOAJ |
| description | Abstract Background Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription factor activity, epigenetic modifications, and changes in gene expression involved are thus complex and still poorly understood. To address this gap, we generated comprehensive reference epigenomes of 8 phenotypically defined subsets of normal human cord blood. Results We describe a striking contraction of H3K27me3 density in differentiated myelo-erythroid cells that resembles a punctate pattern previously ascribed to pluripotent embryonic stem cells. Phenotypically distinct progenitor cell types display a nearly identical repressive H3K27me3 signature characterized by large organized chromatin K27-modification domains that are retained by mature lymphoid cells but lost in terminally differentiated monocytes and erythroblasts. We demonstrate that inhibition of polycomb group members predicted to control large organized chromatin K27-modification domains influences lymphoid and myeloid fate decisions of primary neonatal hematopoietic progenitors in vitro. We further show that a majority of active enhancers appear in early progenitors, a subset of which are DNA hypermethylated and become hypomethylated and induced during terminal differentiation. Conclusion Primitive human hematopoietic cells display a unique repressive H3K27me3 signature that is retained by mature lymphoid cells but is lost in monocytes and erythroblasts. Intervention data implicate that control of this chromatin state change is a requisite part of the process whereby normal human hematopoietic progenitor cells make lymphoid and myeloid fate decisions. |
| first_indexed | 2024-04-12T11:50:26Z |
| format | Article |
| id | doaj.art-323a789235c74537b3d3137709c319fd |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-04-12T11:50:26Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-323a789235c74537b3d3137709c319fd2022-12-22T03:34:11ZengBMCBMC Biology1741-70072022-05-0120112310.1186/s12915-022-01315-1Polycomb contraction differentially regulates terminal human hematopoietic differentiation programsA. Lorzadeh0C. Hammond1F. Wang2D. J. H. F. Knapp3J. CH. Wong4J. Y. A. Zhu5Q. Cao6A. Heravi-Moussavi7A. Carles8M. Wong9Z. Sharafian10J. Steif11M. Moksa12M. Bilenky13P. M. Lavoie14C. J. Eaves15M. Hirst16Department of Microbiology and Immunology, Michael Smith Laboratories, UBCTerry Fox Laboratory, BC CancerTerry Fox Laboratory, BC CancerTerry Fox Laboratory, BC CancerDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCCanada’s Michael Smith Genome Science Centre, BC CancerDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCBC Children’s Hospital Research Institute, Department of Pediatrics, UBCDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCCanada’s Michael Smith Genome Science Centre, BC CancerBC Children’s Hospital Research Institute, Department of Pediatrics, UBCTerry Fox Laboratory, BC CancerDepartment of Microbiology and Immunology, Michael Smith Laboratories, UBCAbstract Background Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription factor activity, epigenetic modifications, and changes in gene expression involved are thus complex and still poorly understood. To address this gap, we generated comprehensive reference epigenomes of 8 phenotypically defined subsets of normal human cord blood. Results We describe a striking contraction of H3K27me3 density in differentiated myelo-erythroid cells that resembles a punctate pattern previously ascribed to pluripotent embryonic stem cells. Phenotypically distinct progenitor cell types display a nearly identical repressive H3K27me3 signature characterized by large organized chromatin K27-modification domains that are retained by mature lymphoid cells but lost in terminally differentiated monocytes and erythroblasts. We demonstrate that inhibition of polycomb group members predicted to control large organized chromatin K27-modification domains influences lymphoid and myeloid fate decisions of primary neonatal hematopoietic progenitors in vitro. We further show that a majority of active enhancers appear in early progenitors, a subset of which are DNA hypermethylated and become hypomethylated and induced during terminal differentiation. Conclusion Primitive human hematopoietic cells display a unique repressive H3K27me3 signature that is retained by mature lymphoid cells but is lost in monocytes and erythroblasts. Intervention data implicate that control of this chromatin state change is a requisite part of the process whereby normal human hematopoietic progenitor cells make lymphoid and myeloid fate decisions.https://doi.org/10.1186/s12915-022-01315-1Human hematopoietic cell differentiationEpigenomicsH3K27me3Hematopoietic progenitorsIn vitro differentiation |
| spellingShingle | A. Lorzadeh C. Hammond F. Wang D. J. H. F. Knapp J. CH. Wong J. Y. A. Zhu Q. Cao A. Heravi-Moussavi A. Carles M. Wong Z. Sharafian J. Steif M. Moksa M. Bilenky P. M. Lavoie C. J. Eaves M. Hirst Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs BMC Biology Human hematopoietic cell differentiation Epigenomics H3K27me3 Hematopoietic progenitors In vitro differentiation |
| title | Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs |
| title_full | Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs |
| title_fullStr | Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs |
| title_full_unstemmed | Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs |
| title_short | Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs |
| title_sort | polycomb contraction differentially regulates terminal human hematopoietic differentiation programs |
| topic | Human hematopoietic cell differentiation Epigenomics H3K27me3 Hematopoietic progenitors In vitro differentiation |
| url | https://doi.org/10.1186/s12915-022-01315-1 |
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