Restricting genomic actions of innate immune mediators on fetal hematopoietic progenitor cells

Tran, Vu; Liu, Peng; Katsumura, Koichi R.; Kim, Erin; Schoff, Bjorn; Johnson, Kirby D.; Bresnick, Emery H.

doi:10.1016/j.isci.2023.106297

Cited by 6 publications

(9 citation statements)

References 103 publications

(144 reference statements)

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“…Loss of GATA2 level/activity triggers an alarm that instigates upregulation of a host of innate immune genes through a mechanism involving derepression of PU.1 transcriptional activity (bottom panel). While genetic analysis demonstrated the vital importance of this mechanism [62 ▪▪ ,66 ▪ ], one cannot rule out the involvement of additional transcriptional regulators, which have not been identified, in GATA2-dependent repression of innate immune genes. Upregulation of IRF8 preferentially promotes monocytic/dendritic cell differentiation of the GATA2-deficient cells, while increased expression of TLR and IL-6 receptor subunits renders the progenitors and their progeny hypersensitive to extrinsic stimuli that activate these receptor systems.…”

Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

“…Loci of many upregulated genes in −77 −/− progenitors are occupied by PU.1 and/or IRF8 at sites of GATA2-regulated chromatin accessibility [42,62 ▪▪ ]. GATA2 represses multiple TLR family members ( Tlr1 , Tlr2 and Tlr6 ) in fetal liver progenitors and HoxB8-immortalized cell lines [66 ▪ ]. PU.1 is implicated in activating Tlr1 and Tlr2 expression [67].…”

Section: Gata2/pu1/interferon-regulatory Factor-8 Axismentioning

confidence: 99%

“…−77 enhancer-mutant fetal liver myeloid progenitors exhibit upregulated expression of Irf8 and other innate immune genes, including TLRs, increased expression of interleukin-6 (IL-6) receptors Il6st and Il6ra , and reduced expression of Csf2rb encoding a subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor that is shared with other cytokine receptors [62 ▪▪ ,66 ▪ ] (Fig. 1).…”

Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

“…In mast cell lines, GATA2 functions through an IL6 enhancer to increase basal and induced IL-6 expression [69]. Compared to −77 −/− progenitors that were rescued by GATA2 expression, HoxB8-immortalized −77 −/− progenitors displayed a more robust induction of Irf8 expression in response to IFNγ and of TLR target genes Tnf and Ccl3 in response to TLR1/2 and TLR2/6 agonists [42,66 ▪ ]. IFNγ-TLR signaling crosstalk further elevated expression of a gene cohort including those encoding cytokines and chemokines.…”

Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

“…1). These changes render the cells hyperresponsive to signaling by IFNγ, IL-6 and TLR1/2 and TLR2/6 agonists and less responsive to GM-CSF [62 ▪▪ ,66 ▪ ]. In mast cell lines, GATA2 functions through an IL6 enhancer to increase basal and induced IL-6 expression [69].…”

Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

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Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function

Johnson

Jung

Tran

et al. 2023

Current Opinion in Hematology

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Purpose of reviewRecent discoveries have provided evidence for mechanistic links between the master regulator of hematopoiesis GATA2 and the key component of interferon and innate immunity signaling pathways, interferon-regulatory factor-8 (IRF8). These links have important implications for the control of myeloid differentiation in physiological and pathological states.Recent findingsGATA2 deficiency resulting from loss of the Gata2 −77 enhancer in progenitors triggers an alarm that instigates the transcriptional induction of innate immune signaling and distorts a myeloid differentiation program. This pathological alteration renders progenitors hyperresponsive to interferon γ, toll-like receptor and interleukin-6 signaling and impaired in granulocyte-macrophage colony-stimulating factor signaling. IRF8 upregulation in −77−/− progenitors promotes monocyte and dendritic cell differentiation while suppressing granulocytic differentiation. As PU.1 promotes transcription of Irf8 and other myeloid and B-lineage genes, GATA2-mediated repression of these genes opposes the PU.1-dependent activating mechanism.SummaryAs GATA2 deficiency syndrome is an immunodeficiency disorder often involving myelodysplastic syndromes and acute myeloid leukemia, elucidating how GATA2 commissions and decommissions genome activity and developmental regulatory programs will unveil mechanisms that go awry when GATA2 levels and/or activities are disrupted.

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Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

Section: Gata2/pu1/interferon-regulatory Factor-8 Axismentioning

confidence: 99%

Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

Section: Inflammation and Loss Of Gata2 In Hematopoietic Stem And Pro...mentioning

confidence: 99%

See 3 more Smart Citations

Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function

Johnson

Jung

Tran

et al. 2023

Current Opinion in Hematology

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Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 gangliosidosis

Allende,

Lee,

Byrnes

et al. 2023

Journal of Lipid Research

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A transcriptional network governing ceramide homeostasis establishes a cytokine-dependent developmental process

Liao,

Babatunde,

Qiu

et al. 2023

Nat Commun

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Transcriptional mechanisms controlling developmental processes establish and maintain proteomic networks, which can govern the levels of intracellular small molecules. Although dynamic changes in bioactive small molecules can link transcription factor and genome activity with cell state transitions, many mechanistic questions are unresolved. Using quantitative lipidomics and multiomics, we discover that the hematopoietic transcription factor GATA1 establishes ceramide homeostasis during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes. Inhibiting a GATA1-induced sphingolipid biosynthetic enzyme, delta(4)-desaturase, or disrupting ceramide homeostasis with cell-permeable dihydroceramide or ceramide is detrimental to erythroid, but not myeloid, progenitor activity. Coupled with genetic editing-based rewiring of the regulatory circuitry, we demonstrate that ceramide homeostasis commissions vital stem cell factor and erythropoietin signaling by opposing an inhibitory protein phosphatase 2A-dependent, dual-component mechanism. Integrating bioactive lipids as essential components of GATA factor mechanisms to control cell state transitions has implications for diverse cell and tissue types.

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Restricting genomic actions of innate immune mediators on fetal hematopoietic progenitor cells

Cited by 6 publications

References 103 publications

Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function

Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function

Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 gangliosidosis

A transcriptional network governing ceramide homeostasis establishes a cytokine-dependent developmental process

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