Lineage selection and self-renewal in a murine multipotent hematopoietic precursor
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ABSTRACT:
PROVIDER: PRJNA1032939 | ENA |
REPOSITORIES: ENA
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Project description:An immortalized multipotent otic progenitor (iMOP) cell was generated by transient expression of c-Myc in Sox2-expressing otic progenitor cells. The procedure activated endogenous c-Myc expression in the cells and amplified existing Sox2-dependent transcripts to promote self-renewal. Downregulation of c-Myc expression following growth factor withdrawal resulted in a molecular switch from self-renewal to otic differentiation. ChIP-Seq was accomplished by immunoprecipitating endogenous RNA PolII, c-Myc and Sox2
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Project description:An immortalized multipotent otic progenitor (iMOP) cell was generated by transient expression of c-Myc in Sox2-expressing otic progenitor cells. The procedure activated endogenous c-Myc expression in the cells and amplified existing Sox2-dependent transcripts to promote self-renewal. Downregulation of c-Myc expression following growth factor withdrawal resulted in a molecular switch from self-renewal to otic differentiation.
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Project description:The mammalian blood system is a hierarchically structured tissue. Hematopoietic stem cells (HSC) reside at the top of this hierarchy and the HSC-derived progenitor cells (HPC) have capacities for both differentiation and self-renewal. Systematic study of the regulatory mechanisms of HSC self-renewal and differentiation is fundamentally important for understanding hematopoiesis and for manipulating HSCs for therapeutic purposes. Herein, the mechanisms regulating HSC biology were studied on a genome-wide scale by integrating epigenomic, transcriptomic, proteomic, and protein-protein interaction data. Previously, we have characterized gene expression and identified important transcription factors (TFs) regulating the switch between self-renewal and differentiation in a multipotent hematopoietic progenitor cell line, EML (Erythroid, Myeloid, and Lymphoid). In the present study, we report binding maps for three additional TFs (SOX4, STAT3, and GABP) that were developed by chromatin immunoprecipitation (ChIP)-Sequencing. Assay for Transposase Accessible Chromatin (ATAC)-Sequencing was applied to globally identify the open chromatin regions associated with TF binding in the self-renewing subpopulation lin-CD34+.Mass spectrometry (MS) was also used to identify proteins and assess differences in their relative abundances. We found that MAPK (Mitogen-activated protein kinase) pathway and JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway components were highly enriched among the binding targets of these TFs in CD34+ cells, and that the TGF-β/SMAD signaling pathway comprised a sub-network of molecules that were differentially expressed between the lin-CD34+ and partially differentiated lin-CD34- cellular states. The present study integrates regulatory information at multiple levels to paint for the first time a more comprehensive picture of the mechanisms underlying the decision between HPC self-renewal and differentiation. We anticipate that this work will provide valuable clues for understanding the molecular switch that controls cell fate decisions between self-renewal or differentiation and blood formation.
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Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation. Three biological replicates of asymmetrically self-renewing cultures (Asym1-3) were compared with cultures that were symmetrically self-renewing - either because they did not express p53 (3 biological replicates, Sym1-3) or they expressed constitutive IMPDH II (i.e., not regulated by p53) as well as p53 (2 biological replicates, Symp53_1 and 2.)
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Project description:Endothelial RNF20 regulates the self-renewal and differentiation of neural precursor cells during embryonic development
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Project description:Pre-leukemic mutations are thought to promote clonal expansion of hematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness. However, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative disease and leukemia. Here we show that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all without immortalizing HSCs or causing leukemia in our experiments. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed HSC cell cycle kinetics using H2B-GFP label retention. We found that NrasG12D had a bimodal effect on HSCs, increasing the proliferation of some HSCs while increasing the quiescence and competitiveness of other HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through a bimodal effect that promotes proliferation in some HSCs and quiescence in others.
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