Gfi1b alters histone methylation at target gene promoters and sites of γ-satellite containing heterochromatin

Vaßen, Lothar; Fiolka, Katharina; Möröy, Tarik

doi:10.1038/sj.emboj.7601124

Cited by 61 publications

(57 citation statements)

References 39 publications

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“…S7). The finding of Megf8 localization in the nucleus was particularly interesting in light of a previous report from a yeast 2-hybrid screen that identified Megf8 as a potential interacting partner of Gfi1b (19), a nuclear protein with known transcription repressor activity and a role in heterochromatinization in erythroid cell lineages (20,21). Double immunostaining showed Megf8/Gfi1b are colocalized as punctate spots in the nucleus (Fig.…”

Section: Megf8 Morpholino Knockdown In Zebrafish Causes Heterotaxymentioning

confidence: 92%

Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy

Zhang

Alpert

Francis

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Forward genetic screens with ENU (N-ethyl-N-nitrosourea) mutagenesis can facilitate gene discovery, but mutation identification is often difficult. We present the first study in which an ENUinduced mutation was identified by massively parallel DNA sequencing. This mutation causes heterotaxy and complex congenital heart defects and was mapped to a 2.2-Mb interval on mouse chromosome 7. Massively parallel sequencing of the entire 2.2-Mb interval identified 2 single-base substitutions, one in an intergenic region and a second causing replacement of a highly conserved cysteine with arginine (C193R) in the gene Megf8. Megf8 is evolutionarily conserved from human to fruit fly, and is observed to be ubiquitously expressed. Morpholino knockdown of Megf8 in zebrafish embryos resulted in a high incidence of heterotaxy, indicating a conserved role in laterality specification. Megf8 C193R mouse mutants show normal breaking of symmetry at the node, but Nodal signaling failed to be propagated to the left lateral plate mesoderm. Videomicroscopy showed nodal cilia motility, which is required for left-right patterning, is unaffected. Although this protein is predicted to have receptor function based on its amino acid sequence, surprisingly confocal imaging showed it is translocated into the nucleus, where it is colocalized with Gfi1b and Baf60C, two proteins involved in chromatin remodeling. Overall, through the recovery of an ENU-induced mutation, we uncovered Megf8 as an essential regulator of left-right patterning.cardiogenesis ͉ left-right ͉ nodal

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Section: Megf8 Morpholino Knockdown In Zebrafish Causes Heterotaxymentioning

confidence: 92%

Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy

Zhang

Alpert

Francis

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…19,[26][27][28] Together these complexes remove transcription-promoting histone modifications and apply repression marks to prevent transcription (Figures 1 and 2). 5,15,26,27,[29][30][31] However, it should be noted that examples have been reported in which Gfi1 and Gfi1b can activate gene expression. 15,18,29,32 Gfi1 and Gfi1b also interact physically with other transcription factors through their zinc fingers to co-regulate gene expression (Figures 1 and 2).…”

Section: Structure and Expression Regulation Of Gfi1 And Gfi1b Proteinsmentioning

confidence: 99%

“…Gfi1b is also part of a complex that contains several other transcription factors. 17,31,36 Gfi1 in neutropenia, myeloid leukemia and hyperinflammatory responses…”

Section: Biological Roles Of Gfi1 and Gfi1bmentioning

confidence: 99%

Gfi1 and Gfi1b: key regulators of hematopoiesis

2010

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Transcription factor Growth factor independence 1 (Gfi1) is required for multilineage blood cell development, from stem and progenitor cells to differentiated lymphoid and myeloid cells. Gfi1 expression is rapidly induced by cytokines that control both the adaptive and innate immune systems. Gfi1 itself represses the expression of genes implicated in cell survival, proliferation and differentiation. Changes in Gfi1 expression and function have not only been implicated in neutropenia, allergy, autoimmunity and hyperinflammatory responses, but also in lymphoma and more recently in the development of leukemia. In this study, we review how Gfi1 and its paralogue Gfi1b control the development of blood cells, discuss how changes in Gfi1 and Gfi1b function contribute to hematological disease and report on the molecular function of these proteins.

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“…Gfi1 can bind consensus DNA target sequences by a C-terminal zinc-finger domain and repress transcription by its N-terminal SNAG domain, 15 in part by recruiting corepressors. [16][17][18][19] Besides acting as a transcriptional repressor, Gfi1 interacts with protein inhibitor of activated signal transducer and activator of transcription (STAT), which can bind to and inhibit STAT3 signaling. 20 As a result, Gfi1 can relieve STAT3 from protein inhibitor of activated STAT3-induced inhibition, resulting in enhanced STAT3 signaling.…”

Section: Introductionmentioning

confidence: 99%

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

Sierra

Sakakibara

Gasperini

et al. 2010

Blood

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The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/ mitogen-activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis

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Gfi1b alters histone methylation at target gene promoters and sites of γ-satellite containing heterochromatin

Cited by 61 publications

References 39 publications

Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy

Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy

Gfi1 and Gfi1b: key regulators of hematopoiesis

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

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