The GATA factor revolution in hematology

Katsumura, Koichi R.; Bresnick, Emery H.

doi:10.1182/blood-2016-09-687871

Cited by 124 publications

(152 citation statements)

References 180 publications

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“…By contrast, Inpp5d and Pstpip1 composite elements were not GATA-2-, Scl/TAL1- or Lmo2-occupied (Figure S6B). Consistent with the established paradigm in which only certain GATA-2-regulated genes are GATA-1-regulated (Dore et al, 2012; Fujiwara et al, 2009; Katsumura et al, 2017), a subset of +9.5-like loci ( Samd14, Bcl2l1 , and Bag2 ) are GATA-1-regulated in G1E cells; others ( Sox6, Trip4, Inpp5d and Pstpip1 ) are GATA-1-insensitive (Figure S7A). To test whether the +9.5-like loci are anemia-responsive, we quantified gene expression in spleen from control and PHZ-treated mice.…”

Section: Resultssupporting

confidence: 82%

GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia

et al. 2017

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SUMMARY An enhancer with amalgamated E-box and GATA motifs (+9.5) controls expression of the regulator of hematopoiesis GATA-2. While similar GATA-2-occupied elements are common in the genome, occupancy does not predict function, and GATA-2-dependent genetic networks are incompletely defined. A “+9.5-like” element resides in an intron of Samd14 (Samd14-Enh) encoding a sterile alpha motif (SAM) domain protein. Deletion of Samd14-Enh in mice strongly decreased Samd14 expression in bone marrow and spleen. Although steady-state hematopoiesis was normal, Samd14-Enh-/- mice died in response to severe anemia. Samd14-Enh stimulated Stem Cell Factor/c-Kit signaling, which promotes erythrocyte regeneration. Anemia activated Samd14-Enh by inducing enhancer components and enhancer chromatin accessibility. Thus, a GATA-2/anemia-regulated enhancer controls expression of a SAM domain protein that confers survival in anemia. We propose that Samd14-Enh and an ensemble of anemia-responsive enhancers are essential for erythrocyte regeneration in stress erythropoiesis, a vital process in pathologies including β-thalassemia, myelodysplastic syndrome and viral infection.

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Section: Resultssupporting

confidence: 82%

GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia

et al. 2017

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“…Recurring GATA2 mutations in cancer, immunological and vascular/lymphatic disorders highlight critical GATA-2 functions in human biology and pathology (Dickinson et al, 2014; Katsumura et al, 2017; Spinner et al, 2014). Since GATA2 mutations impair DNA binding (Hahn et al, 2011; Katsumura et al, 2016; Katsumura et al, 2014) or reduce GATA-2 expression (Hsu et al, 2013; Johnson et al, 2012), and elevated GATA2 expression can correlate with poor prognosis of AML (Vicente et al, 2012), strict control of GATA-2 levels/activity ensures normal hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

“…The Gata2 enhancers had both functional similarities and differences in vivo . As mutation or disruption via chromosomal rearrangement of both enhancers are implicated in human MDS and AML, and other pathologies (Groschel et al, 2014; Hsu et al, 2013; Johnson et al, 2012; Katsumura et al, 2017; Yamazaki et al, 2014), insights from this model will inform human enhanceropathies.…”

Section: Discussionmentioning

confidence: 99%

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

et al. 2017

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SUMMARY Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies including leukemia. GATA-2-regulated enhancers regulate Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. The +9.5 kb enhancer activates transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion abrogates HSC generation. The −77 kb enhancer activates transcription in myeloid progenitors, and its deletion impairs differentiation. Since +9.5−/− embryos are HSC-deficient, it was unclear whether the +9.5 functions in progenitors or if GATA-2 expression in progenitors solely requires −77. We further dissected the mechanisms using −77;+9.5 compound heterozygous (CH) mice. The embryonic lethal CH mutation depleted megakaryocyte-erythrocyte progenitors (MEPs). While the +9.5 suffices for HSC generation, the −77 and +9.5 must reside on one allele to induce MEPs. The −77 generated Burst Forming Unit-Erythroid through induction of GATA-1 and other GATA-2 targets. The enhancer circuits controlled signaling pathways that orchestrate a GATA factor-dependent blood development program.

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“…GATA-1 is a DNA binding protein that is responsible for recognition of a sequence motif within promoters and enhancers of numerous erythroid-expressed genes. 49–51 GATA-1 mediates the temporal regulation and coordination of gene expression in erythroid and megakaryocytic lineages.…”

Section: Mitochondrial Iron Metabolismmentioning

confidence: 99%

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

Kafina

Paw

2017

Metallomics

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Vertebrate red blood cells (RBCs) arise from erythroblasts in the human bone marrow through a process known as erythropoiesis. Iron uptake is a crucial hallmark, essential for heme biosynthesis in the differentiating erythroblasts, which are dedicated to producing hemoglobin. Erythropoiesis is facilitated by a network of intracellular transport proteins, chaperones, and circulating hormones. Intracellular iron is targeted to the mitochondria for incorporation into a porphyrin ring to form heme and cytosolic iron-sulfur proteins, including Iron Regulatory Protein 1 (IRP1). These processes are tightly regulated to prevent both excess and insufficient levels of iron and heme precursors. Crosstalk between the heme and iron-sulfur synthesizing pathways has been demonstrated to serve as a regulatory feedback mechanism. The activity of δ-aminolevulinic acid synthase (ALAS), the first and rate-limiting enzyme of heme biosynthesis, is a fundamental node of this regulation. Recently, the mitochondrial unfoldase, ClpX, has received attention as a novel key player that modulates this step in heme biogenesis, implicating a role in the pathophysiology of anemic diseases. This chapter reviews the canonical pathways in intracellular iron and heme trafficking and recent findings of iron and heme metabolism in vertebrate red cells. A discussion of the molecular approaches to studying iron and heme transport is provided to highlight opportunities for revealing therapeutic targets.

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The GATA factor revolution in hematology

Cited by 124 publications

References 180 publications

GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia

GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

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