Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Generation of hematopoietic progenitor cell lines with myeloid and lymphoid potential using a conditional form of Hoxb8

ABSTRACT: Investigation of immune cell differentiation and function is limited by shortcomings of suitable and scalable experimental systems. Although forced expression of certain Hox genes allows immortalization of hematopoietic progenitor cells, their differentiation potential is limited to select myeloid lineages. Here we show that an estrogen-regulated form of Hoxb8 that is retrovirally delivered into bone marrow cells can be used along with FLT3 ligand to conditionally immortalize early hematopoietic progenitor cells (Hoxb8-FL). Hoxb8-FL cells have lost self-renewal capacity and the ability to adopt megakaryocyte/ erythroid lineage fates, but sustain myeloid and lymphoid differentiation potential. Hoxb8-FL cells differentiate in vitro and in vivo into different myeloid and lymphoid cell types, including macrophages, granulocytes, dendritic cells and B- and T-lymphocytes, which are phenotypically and functionally indistinguishable from their primary counterparts. Given the simplicity to generate Hoxb8-FL cells and their unlimited proliferative capacity, this system provides unique opportunities to investigate cell differentiation and immune cell functions. Hoxb8 expressing immortalized cells

ORGANISM(S): Mus musculus

SUBMITTER: David Finkelstein

PROVIDER: E-GEOD-45759 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Collombet2016 - Lymphoid and myeloid cell specification and transdifferentiation This model is described in the article: Logical modeling of lymphoid and myeloid cell specification and transdifferentiation Samuel Collombet, Chris van Oevelen, Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis Thieffry Proceedings of the National Academy of Sciences of the United States of America Abstract: Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions. This model is hosted on BioModels Database and identified by: MODEL1610240000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Epigenetic modifications must underlie lineage-specific differentiation since terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Hematopoiesis provides a well-defined model of progressive differentiation in which to study the role of epigenetic modifications in cell fate decisions. Multi-potent progenitors (MPPs) can differentiate into all blood cell lineages, while downstream progenitors commit to either myeloerythroid or lymphoid lineages. While DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs {Broske, 2009 #6}, a comprehensive DNA methylation map of hematopoietic progenitors, or of any cell lineage, does not exist. Here we have generated a mouse DNA methylation map, examining 4.6 million CpG sites throughout the genome including all CpG islands and shores, examining MPPs, all lymphoid progenitors (ALPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Interestingly, differentiation towards the myeloid lineage corresponds with a net decrease in DNA methylation, while lymphoid commitment involves a net increase in DNA methylation, but both show substantial dynamic changes consistent with epigenetic plasticity during development. By comparing lineage-specific DNA methylation to gene expression array data, we find many examples of genes and pathways not previously known to be involved in lymphoid/myeloid differentiation, such as Gcnt2, Arl4c, Gadd45α, and Jdp2. Several transcription factors, including Meis1 and Prdm16 were methylated and silenced during differentiation, suggesting a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome appears to be important in hematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation, often correlating with gene expression changes, and define a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions. mRNA expression of 8 hematopoietic progenitor populations [MPPFL-(5), MPPFL+(3), CMP(3), GMP(3), CLP(3), DN1(3), DN2(3), DN3(3)] were compared

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Generation of hematopoietic progenitor cell lines with myeloid and lymphoid potential using a conditional form of Hoxb8

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