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A large gene network in immature erythroid cells is controlled by the myeloid and B cell transcriptional regulator PU.1.

Wontakal SN, Guo X, Will B, Shi M, Raha D, Mahajan MC, Weissman S, Snyder M, Steidl U, Zheng D, Skoultchi AI - PLoS Genet. (2011)

Bottom Line: PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1.By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo.Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages.

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PU.1 regulates many genes in the PI3K/Akt and ERK/MAPK signaling pathways.(A) and (B) IPA analysis was performed as described in Materials and Methods on PU.1 target genes in both ES-EP and MEL cells. The PI3K/Akt and ERK/MAPK signaling pathways were identified as being significantly over-represented among those genes. The left part of each panel depicts all of the components of the indicated IPA pathway. Components denoted with a filled yellow circle indicate that the gene for that component is associated with a PU.1 ChIP-Seq peak in both ES-EP and MEL cells. To the right of each pathway is shown the results of gene expression analysis of the indicated genes in early erythroid progenitors derived from wild-type embryos relative to PU.1 low embryos.
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pgen-1001392-g005: PU.1 regulates many genes in the PI3K/Akt and ERK/MAPK signaling pathways.(A) and (B) IPA analysis was performed as described in Materials and Methods on PU.1 target genes in both ES-EP and MEL cells. The PI3K/Akt and ERK/MAPK signaling pathways were identified as being significantly over-represented among those genes. The left part of each panel depicts all of the components of the indicated IPA pathway. Components denoted with a filled yellow circle indicate that the gene for that component is associated with a PU.1 ChIP-Seq peak in both ES-EP and MEL cells. To the right of each pathway is shown the results of gene expression analysis of the indicated genes in early erythroid progenitors derived from wild-type embryos relative to PU.1 low embryos.

Mentions: IPA analysis also revealed several important cellular pathways that are regulated by PU.1 in erythroid cells. For example, 58% (79/137) of genes involved in the PI3K/Akt signaling pathway are occupied by PU.1 in ES-EP and MEL cells (Figure 5A). Gene expression analysis of wild-type and PU.1 low erythroid progenitors indicates that many genes that stimulate this pathway are positively regulated by PU.1 (Figure 5A). Another pathway found to be regulated by PU.1 in erythroid cells is the ERK/MAPK signaling pathway. 48% (92/192) of the genes in this IPA pathway are occupied by PU.1 (Figure 5B). As with the PI3K signaling pathway, gene expression analysis shows that PU.1 upregulates many genes that stimulate ERK/MAPK signaling (Figure 5B). IPA analysis also showed that PU.1 regulates the Jak/Stat signaling pathway. 67% (43/64) of the genes in this pathway are occupied by PU.1, and many of these genes are upregulated by PU.1 (data not shown). As discussed below, the PI3K/Akt, ERK/MAPK, and Jak/Stat signaling pathways have all been shown to play important roles in erythroid cell proliferation, survival and differentiation. Therefore, these results indicate that PU.1 regulates many genes and pathways that are crucial for erythroid cell function.


A large gene network in immature erythroid cells is controlled by the myeloid and B cell transcriptional regulator PU.1.

Wontakal SN, Guo X, Will B, Shi M, Raha D, Mahajan MC, Weissman S, Snyder M, Steidl U, Zheng D, Skoultchi AI - PLoS Genet. (2011)

PU.1 regulates many genes in the PI3K/Akt and ERK/MAPK signaling pathways.(A) and (B) IPA analysis was performed as described in Materials and Methods on PU.1 target genes in both ES-EP and MEL cells. The PI3K/Akt and ERK/MAPK signaling pathways were identified as being significantly over-represented among those genes. The left part of each panel depicts all of the components of the indicated IPA pathway. Components denoted with a filled yellow circle indicate that the gene for that component is associated with a PU.1 ChIP-Seq peak in both ES-EP and MEL cells. To the right of each pathway is shown the results of gene expression analysis of the indicated genes in early erythroid progenitors derived from wild-type embryos relative to PU.1 low embryos.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111485&req=5

pgen-1001392-g005: PU.1 regulates many genes in the PI3K/Akt and ERK/MAPK signaling pathways.(A) and (B) IPA analysis was performed as described in Materials and Methods on PU.1 target genes in both ES-EP and MEL cells. The PI3K/Akt and ERK/MAPK signaling pathways were identified as being significantly over-represented among those genes. The left part of each panel depicts all of the components of the indicated IPA pathway. Components denoted with a filled yellow circle indicate that the gene for that component is associated with a PU.1 ChIP-Seq peak in both ES-EP and MEL cells. To the right of each pathway is shown the results of gene expression analysis of the indicated genes in early erythroid progenitors derived from wild-type embryos relative to PU.1 low embryos.
Mentions: IPA analysis also revealed several important cellular pathways that are regulated by PU.1 in erythroid cells. For example, 58% (79/137) of genes involved in the PI3K/Akt signaling pathway are occupied by PU.1 in ES-EP and MEL cells (Figure 5A). Gene expression analysis of wild-type and PU.1 low erythroid progenitors indicates that many genes that stimulate this pathway are positively regulated by PU.1 (Figure 5A). Another pathway found to be regulated by PU.1 in erythroid cells is the ERK/MAPK signaling pathway. 48% (92/192) of the genes in this IPA pathway are occupied by PU.1 (Figure 5B). As with the PI3K signaling pathway, gene expression analysis shows that PU.1 upregulates many genes that stimulate ERK/MAPK signaling (Figure 5B). IPA analysis also showed that PU.1 regulates the Jak/Stat signaling pathway. 67% (43/64) of the genes in this pathway are occupied by PU.1, and many of these genes are upregulated by PU.1 (data not shown). As discussed below, the PI3K/Akt, ERK/MAPK, and Jak/Stat signaling pathways have all been shown to play important roles in erythroid cell proliferation, survival and differentiation. Therefore, these results indicate that PU.1 regulates many genes and pathways that are crucial for erythroid cell function.

Bottom Line: PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1.By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo.Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages.

Show MeSH