Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond

Bresnick, Emery H.; Hewitt, Kyle J.; Mehta, Charu; Keleş, Sündüz; Paulson, Robert F.; Johnson, Kirby D.

doi:10.1242/dev.151423

Cited by 114 publications

(40 citation statements)

References 220 publications

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“…While symptoms can present in young children, adults can be asymptomatic, roid precursors, GATA-2 induces Gata1 and Kit transcription (50). GATA-1 represses Kit transcription (52,53) to promote prodifferentiation erythropoietin signaling (54) and represses Gata2 transcription (43,(55)(56)(57). In HSPCs, GATA-2 induces 20 G protein-coupled receptors, including GPR65 (58).…”

Section: Ddx41 Srp72mentioning

confidence: 99%

Transcription factor mutations as a cause of familial myeloid neoplasms

Churpek¹,

Bresnick²

2019

Journal of Clinical Investigation

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Section: Ddx41 Srp72mentioning

confidence: 99%

Transcription factor mutations as a cause of familial myeloid neoplasms

Churpek¹,

Bresnick²

2019

Journal of Clinical Investigation

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“…It was not possible to use −77 −/− bone marrow, because this homozygous mutation is embryonic-lethal (20). Genetic complementation analysis in mutant cells is a powerful strategy to dissect mechanisms, as exemplified by studies with GATA-1 (48)(49)(50)(51). While the MAE system enables quantification of GATA-2 activity to regulate endogenous target genes (31), no GATA-2 genetic complementation systems have been described.…”

Section: Gata-2 N-finger Increases Gata-2 Endogenous Target Gene Chromentioning

confidence: 99%

Human leukemia mutations corrupt but do not abrogate GATA-2 function

Katsumura

Mehta

Hewitt

et al. 2018

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

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By inducing the generation and function of hematopoietic stem and progenitor cells, the master regulator of hematopoiesis GATA-2 controls the production of all blood cell types. Heterozygous GATA2 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA2 disease mutations commonly disrupt amino acid residues that mediate DNA binding or cis-elements within a vital GATA2 intronic enhancer, suggesting a haploinsufficiency mechanism of pathogenesis. Mutations also occur in GATA2 coding regions distinct from the DNA-binding carboxyl-terminal zinc finger (C-finger), including the amino-terminal zinc finger (N-finger), and N-finger function is not established. Whether distinct mutations differentially impact GATA-2 mechanisms is unknown. Here, we demonstrate that N-finger mutations decreased GATA-2 chromatin occupancy and attenuated target gene regulation. We developed a genetic complementation assay to quantify GATA-2 function in myeloid progenitor cells from Gata2 −77 enhancer-mutant mice. GATA-2 complementation increased erythroid and myeloid differentiation. While GATA-2 disease mutants were not competent to induce erythroid differentiation of Lin−Kit+ myeloid progenitors, unexpectedly, they promoted myeloid differentiation and proliferation. As the myelopoiesis-promoting activity of GATA-2 mutants exceeded that of GATA-2, GATA2 disease mutations are not strictly inhibitory. Thus, we propose that the haploinsufficiency paradigm does not fully explain GATA-2–linked pathogenesis, and an amalgamation of qualitative and quantitative defects instigated by GATA2 mutations underlies the complex phenotypes of GATA-2–dependent pathologies.

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“…Coding and non-coding GATA2 mutations cause GATA2-deficiency syndromes, which often involve immunodeficiency and predisposition to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) (15,(44)(45)(46)(47)(48). Gata2 and Samd14 transcription are both controlled by enhancers harboring a nearly identical conserved Ebox-spacer-GATA composite element, and the study of these and related enhancers established a GATA2 and anemia-activated genetic network with many potentially critical network constituents (2,20). GATA2 strongly and directly activates Samd14 transcription, and Samd14 facilitates SCF/c-Kit signaling during hematopoiesis and survival of stress erythroid progenitors.…”

Section: Discussionmentioning

confidence: 99%

“…Erythrocyte developmental mechanisms can differ during embryogenesis, adult homeostasis, and regenerative responses to injury or stress (1,2). In anemia, the increased erythropoiesis demand is met by augmented erythroid progenitor activity in the bone marrow or at extramedullary sites (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Sterile α-motif domain requirement for cellular signaling and survival

Ray

Chee

Matson

et al. 2020

Journal of Biological Chemistry

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Hundreds of sterile α-motif (SAM) domains have predicted structural similarities and are reported to bind proteins, lipids, or RNAs. However, the majority of these domains have not been analyzed functionally. Previously, we demonstrated that a SAM domain-containing protein, SAMD14, promotes SCF/proto-oncogene c-Kit (c-Kit) signaling, erythroid progenitor function, and erythrocyte regeneration. Deletion of a Samd14 enhancer (Samd14–Enh), occupied by GATA2 and SCL/TAL1 transcription factors, reduces SAMD14 expression in bone marrow and spleen and is lethal in a hemolytic anemia mouse model. To rigorously establish whether Samd14–Enh deletion reduces anemia-dependent c-Kit signaling by lowering SAMD14 levels, we developed a genetic rescue assay in murine Samd14–Enh−/− primary erythroid precursor cells. SAMD14 expression at endogenous levels rescued c-Kit signaling. The conserved SAM domain was required for SAMD14 to increase colony-forming activity, c-Kit signaling, and progenitor survival. To elucidate the molecular determinants of SAM domain function in SAMD14, we substituted its SAM domain with distinct SAM domains predicted to be structurally similar. The chimeras were less effective than SAMD14 itself in rescuing signaling, survival, and colony-forming activities. Thus, the SAMD14 SAM domain has attributes that are distinct from other SAM domains and underlie SAMD14 function as a regulator of cellular signaling and erythrocyte regeneration.

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Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond

Cited by 114 publications

References 220 publications

Transcription factor mutations as a cause of familial myeloid neoplasms

Transcription factor mutations as a cause of familial myeloid neoplasms

Human leukemia mutations corrupt but do not abrogate GATA-2 function

Sterile α-motif domain requirement for cellular signaling and survival

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