Gfi1 and Gfi1b: key regulators of hematopoiesis

Meer, Laurens T. van der; Jansen, Joop H.; Reijden, Bert A. van der

doi:10.1038/leu.2010.195

Cited by 185 publications

(166 citation statements)

References 106 publications

(160 reference statements)

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“…Intriguingly, a hallmark of Gfi1-null mice is inhibited granulocytic differentiation together with enhanced monocytic differentiation. 43 Gfi1-null mice further display myeloid progenitor expansion associated with Hoxa9 overexpression, 28 similar to our LSD1-kd model. As Gfi1 and LSD1 are known to directly interact 11 and LSD1-kd mice mirror myeloid abnormalities of Gfi1-deficient mice, LSD1 presumably represents a key mediator of Gfi1 function in myelopoiesis.…”

Section: Discussionsupporting

confidence: 73%

“…It was shown that Gfi1 and Gfi1b are both negative regulators of HSC proliferation. 43 However, Gfi1-deficient HSCs displayed impaired self-renewal capacity in competitive repopulation assays whereas the self-renewal of Gfi1b-deficient HSCs remained unaltered. 40 Interestingly, conditional deletion of Gfi1b resulted in expanded phenotypic HSCs, which parallels our findings in LSD1-kd mice.…”

Section: Discussionmentioning

confidence: 99%

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Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

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“…Consistent with a prosurvival role of Gfi1 observed in other cell types (8,21), deficiency of Gfi1 modestly elevated apoptosis of CD4SP thymocytes and rendered them a competitive disadvantage. However, forced expression of the Bcl2 transgene or deletion of Bim did not affect the generation of nT reg cells in Gfi1 CD4 mice.…”

Section: Discussionsupporting

confidence: 49%

“…S1A). Given a prominent role of Gfi1 in the development of multiple hematopoietic lineages (8,21), it remained possible that the expansion of Gfi1 −/− nT reg cells was secondary to defective early development and/or influences by nonlymphoid cells. Hence, we crossed loxPflanked Gfi1 alleles (Gfi1 fl/fl ) with two Cre lines, the hCD2-iCre and CD4-Cre transgenic mice, in which Cre expression was initiated at the early and late DN stages, respectively (called Gfi1 hCD2 and Gfi1 CD4 ) (22,23).…”

Section: Gfi1mentioning

confidence: 99%

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Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells

Shi¹,

Kalupahana²,

Turnis³

et al. 2013

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

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Foxp3 + regulatory T (T reg ) cells are essential for the maintenance of self-tolerance and immune homeostasis. The majority of T reg cells is generated in the thymus as a specific subset of CD4 + T cells, known as thymus-derived or natural T reg (nT reg ) cells, in response to signals from T-cell receptors, costimulatory molecules, and cytokines. Recent studies have identified intracellular signaling and transcriptional pathways that link these signals to Foxp3 induction, but how the production of these extrinsic factors is controlled remains poorly understood. Here, we report that the transcription repressor growth factor independent 1 (Gfi1) has a key inhibitory role in the generation of nT reg cells by a noncell-autonomous mechanism. T cell-specific deletion of Gfi1 results in aberrant expansion of thymic nT reg cells and increased production of cytokines. In particular, IL-2 overproduction plays an important role in driving the expansion of nT reg cells. In contrast, although Gfi1 deficiency elevated thymocyte apoptosis, Gfi1 repressed nT reg generation independently of its prosurvival effect. Consistent with an inhibitory role of Gfi1 in this process, loss of Gfi1 dampens antitumor immunity. These data point to a previously unrecognized extrinsic control mechanism that negatively shapes thymic generation of nT reg cells.

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KDM1 class flavin‐dependent protein lysine demethylases

et al. 2015

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Flavin-dependent, lysine-specific protein demethylases (KDM1s) are a subfamily of amine oxidases that catalyze the selective posttranslational oxidative demethylation of methyllysine side chains within protein and peptide substrates. KDM1s participate in the widespread epigenetic regulation of both normal and disease state transcriptional programs. Their activities are central to various cellular functions, such as hematopoietic and neuronal differentiation, cancer proliferation and metastasis, and viral lytic replication and establishment of latency. Interestingly, KDM1s function as catalytic subunits within complexes with coregulatory molecules that modulate enzymatic activity of the demethylases and coordinate their access to specific substrates at distinct sites within the cell and chromatin. Although several classes of KDM1 -selective small molecule inhibitors have been recently developed, these pan-active site inhibition strategies lack the ability to selectively discriminate between KDM1 activity in specific, and occasionally opposing, functional contexts within these complexes. Here we review the discovery of this class of demethylases, their structures, chemical mechanisms, and specificity. Additionally, we review inhibition of this class of enzymes as well as emerging interactions with coregulatory molecules that regulate demethylase activity in highly specific functional contexts of biological and potential therapeutic importance.

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Gfi1 and Gfi1b: key regulators of hematopoiesis

Cited by 185 publications

References 106 publications

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells

KDM1 class flavin‐dependent protein lysine demethylases

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