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Functional and molecular characterization of mouse Gata2-independent hematopoietic progenitors

ABSTRACT: The Gata2 transcription factor is a pivotal regulator of hematopoietic stem cell (HSC) development and maintenance. Gata2 functions in the embryo during endothelial cell to hematopoietic cell transition (EHT) to affect hematopoietic cluster, HPC and HSC formation. Although previous studies of cell populations phenotypically enriched in HPCs and HSCs show expression of Gata2, there has been no direct study of Gata2 expressing cells during normal hematopoiesis. In this study we generate a Gata2 Venus reporter mouse model with unperturbed Gata2 expression to examine the hematopoietic function and transcriptome of Gata2 expressing and nonexpressing cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE76254 | GEO | 2015/12/22

SECONDARY ACCESSION(S): PRJNA306727

REPOSITORIES: GEO

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Functional and molecular characterization of mouse Gata2-independent hematopoietic progenitors

Project description:The Gata2 transcription factor is a pivotal regulator of hematopoietic stem cell (HSC) development and maintenance. Gata2 functions in the embryo during endothelial cell to hematopoietic cell transition (EHT) to affect hematopoietic cluster, HPC and HSC formation. Although previous studies of cell populations phenotypically enriched in HPCs and HSCs show expression of Gata2, there has been no direct study of Gata2 expressing cells during normal hematopoiesis. In this study we generate a Gata2 Venus reporter mouse model with unperturbed Gata2 expression to examine the hematopoietic function and transcriptome of Gata2 expressing and nonexpressing cells. Gata2Venus- HPCs 1 replicate, Gata2Venus+ HPCs 1 replicate

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Project description:Latexin is a hematopoietic stem cells (HSCs) and progenitor cells (HPCs) regulatory gene. Its deletion leads to the expansion of HSC and HPC population. The underlying mechanims are largely unknown. We therefore perfored microarrary analysis in HPCs with (Lxn-/-) and without (wild-type, WT) latexin deletion, and determined genes that were altered by latexin deletion. This led us to identify the molecular mechanims by which latexin regulates HSC function.

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A network including TGFÎ²/Smad4, Gata2 and p57 regulates proliferation of mouse hematopoietic stem/progenitor cells [expression]

Project description:Transforming growth factor-Î² (TGFÎ²) is a potent inhibitor of hematopoietic stem cell (HSC) proliferation. However, the precise mechanism for this effect is unknown. Here, we have identified the transcription factor Gata2, previously described as an important regulator of HSC function, as an early and direct target gene for TGFÎ²-induced Smad signaling in hematopoietic stem and progenitor cells (HSPCs). Interestingly, TGFÎ²-induced Gata2 upregulation is critical for subsequent transcriptional activation of the TGFÎ² signaling effector molecule p57 and resulting growth arrest of HSPCs. Importantly, both Gata2 and p57 are abundantly expressed in freshly isolated highly purified HSCs, demonstrating the relevance of this circuit in HSC regulation within the HSC niche. Our results connect key molecules involved in HSC self-renewal and reveal a functionally relevant network regulating proliferation of primitive hematopoietic cells. To identify early gene targets of TGFÎ² signaling in hematopoietic progenitor cells, we performed high-throughput gene expression profiling of a primitive murine hematopoietic cell line. One of the revealed target genes was the transcription factor Gata2, which became the base for the rest of the study. Three independent RNA harvests were separately analyzed. Untreated cells were used as controls to the 10ng/ml TGFb-treated cells.

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A network including TGFÎ²/Smad4, Gata2 and p57 regulates proliferation of mouse hematopoietic stem/progenitor cells [ChIP-seq]

Project description:Transforming growth factor-Î² (TGFÎ²) is a potent inhibitor of hematopoietic stem cell (HSC) proliferation. However, the precise mechanism for this effect is unknown. Here, we have identified the transcription factor Gata2, previously described as an important regulator of HSC function, as an early and direct target gene for TGFÎ²-induced Smad signaling in hematopoietic stem and progenitor cells (HSPCs). Interestingly, TGFÎ²-induced Gata2 upregulation is critical for subsequent transcriptional activation of the TGFÎ² signaling effector molecule p57 and resulting growth arrest of HSPCs. Importantly, both Gata2 and p57 are abundantly expressed in freshly isolated highly purified HSCs, demonstrating the relevance of this circuit in HSC regulation within the HSC niche. Our results connect key molecules involved in HSC self-renewal and reveal a functionally relevant network regulating proliferation of primitive hematopoietic cells. To identify TGFÎ² targets downstream of Gata2, we carried out a ChIP-Seq experiment on TGFÎ²-induced Lhx2 cells. Interestingly, there was a large overlap between the GATA2-bound genes and genes differentially expressed after 2h TGFÎ² induction. One sample of 1x10^8 cells (treated with 10 ng/ml TGFÎ² for 2h) was sequenced.

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