GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

Zwifelhofer, Nicole M.; Cai, Xiaoli; Liao, Ruiqi; Mao, Bin; Conn, Daniel; Mehta, Charu; Keleş, Sündüz; Xia, Yang; Bresnick, Emery H.

doi:10.1371/journal.pgen.1009286

Cited by 15 publications

(23 citation statements)

References 68 publications

(124 reference statements)

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“…Although monocytopenia is common in GATA2 deficiency syndrome that emerges in children or adults, bone marrow macrophages persist 23 . Many GATA2-regulated genes have been described in diverse systems 1,[22][23][24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

GATA2 deficiency elevates interferon regulatory factor-8 to subvert a progenitor cell differentiation program

Johnson¹,

Soukup

Bresnick

2022

Blood Advances

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Cell type-specific transcription factors control stem and progenitor cell transitions by establishing networks containing hundreds of genes and proteins. Network complexity renders it challenging to discover essential versus modulatory or redundant components. This scenario is exemplified by GATA2 regulation of hematopoiesis during embryogenesis. Loss of a far upstream Gata2 enhancer (-77) disrupts the GATA2-dependent transcriptome governing hematopoietic progenitor cell differentiation. The aberrant transcriptome includes the transcription factor Interferon Regulatory Factor-8 and a host of innate immune regulators. Mutant progenitors lose the capacity to balance production of diverse hematopoietic progeny. To elucidate mechanisms, we asked if IRF8 is essential, contributory or not required. Reducing Irf8, in the context of the -77 mutant allele, reversed granulocytic deficiencies and the excessive accumulation of dendritic cell committed progenitors. Despite many dysregulated components that control vital transcriptional, signaling and immune processes, the aberrant elevation of a single transcription factor deconstructed the differentiation program.

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Section: Introductionmentioning

confidence: 99%

GATA2 deficiency elevates interferon regulatory factor-8 to subvert a progenitor cell differentiation program

Johnson¹,

Soukup

Bresnick

2022

Blood Advances

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“…GATA1 utilizes the histone methyltransferase and corepressor SetD8 at select target genes, and SetD8 promotes erythroblast survival in CD71 + Ter119 + murine erythroblasts ( 60–62 ). GATA1 induces expression of the equilibrative nucleoside transporter Slc29a1 that transports adenosine ( 63 ). Slc29a1 regulates adenosine-dependent processes and confers erythroblast survival ( 63 ).…”

Section: Discussionmentioning

confidence: 99%

“…GATA1 induces expression of the equilibrative nucleoside transporter Slc29a1 that transports adenosine ( 63 ). Slc29a1 regulates adenosine-dependent processes and confers erythroblast survival ( 63 ). SCF activates c-Kit signaling, which synergizes with EpoR signaling to promote survival and proliferation of erythroblasts ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis

Mehta

Andrade

Matson

et al. 2021

Nucleic Acids Research

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Cellular differentiation requires vast remodeling of transcriptomes, and therefore machinery mediating remodeling controls differentiation. Relative to transcriptional mechanisms governing differentiation, post-transcriptional processes are less well understood. As an important post-transcriptional determinant of transcriptomes, the RNA exosome complex (EC) mediates processing and/or degradation of select RNAs. During erythropoiesis, the erythroid transcription factor GATA1 represses EC subunit genes. Depleting EC structural subunits prior to GATA1-mediated repression is deleterious to erythroid progenitor cells. To assess the importance of the EC catalytic subunits Dis3 and Exosc10 in this dynamic process, we asked if these subunits function non-redundantly to control erythropoiesis. Dis3 or Exosc10 depletion in primary murine hematopoietic progenitor cells reduced erythroid progenitors and their progeny, while sparing myeloid cells. Dis3 loss severely compromised erythroid progenitor and erythroblast survival, rendered erythroblasts hypersensitive to apoptosis-inducing stimuli and induced γ-H2AX, indicative of DNA double-stranded breaks. Dis3 loss-of-function phenotypes were more severe than those caused by Exosc10 depletion. We innovated a genetic rescue system to compare human Dis3 with multiple myeloma-associated Dis3 mutants S447R and R750K, and only wild type Dis3 was competent to rescue progenitors. Thus, Dis3 establishes a disease mutation-sensitive, cell type-specific survival mechanism to enable a differentiation program.

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“…Transport of nucleosides into HSCs is dependent on nucleoside transporters and ENT1 is the major membrane transporter of adenosine in HSCs [29,30]. GATA transcription factors, which actuate genetic networks in HSCs, erythroid precursor cells, and other erythroid cells [31], regulate many membrane transporters, including ENT1 during erythropoiesis [32]. Slc29a1−/− mice had macrocytosis, anaemia, and reduced numbers of erythroid progenitors in the bone marrow [33].…”

Section: Disease Associationsmentioning

confidence: 99%

Augustine Blood Group System and Equilibrative Nucleoside Transporter 1

Daniels¹

2021

Transfus Med Hemother

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Augustine (AUG) is a blood group system comprising four antigens: AUG1, AUG2 (Ata), and AUG4 are of very high frequency; AUG3 is of very low frequency. These antigens are located on ENT1, an equilibrative nucleoside transporter encoded by SLC19A1. AUG antibodies are of clinical relevance in blood transfusion and pregnancy: anti-AUG2 have caused haemolytic transfusion reactions; the only anti-AUG3 was associated with severe haemolytic disease of the fetus and newborn. ENT1 is present in almost all human tissues. It facilitates the transfer of purine and pyrimidine nucleosides and is responsible for the majority of adenosine transport across plasma membranes. Adenosine transport appears to be an important factor in the regulation of bone metabolism. The AUGnull phenotype (AUG:–1,–2,–3,–4) has been found in three siblings, who are homozygous for an inactivating splice-site mutation in SLC29A1. Although ENT1 is very likely to be absent from all cells in these three individuals, they were apparently healthy with normal lifestyles. However, they suffered frequent attacks of pseudogout, a form of arthritis, in various joints with multiple calcifications around their hand joints. Ectopic calcification in the hips, pubic symphysis, and lumbar discs was present in the propositus. The three AUGnull individuals had misshapen red cells with deregulated protein phosphorylation, but no anaemia or shortening of red cell lifespan. Defective in vitro erythropoiesis in the absence of ENT1 was confirmed by shRNA-mediated knockdown of ENT1 during in vitro erythropoiesis of CD34+ progenitor cells from individuals with normal ENT1. Nucleoside transporters, such as ENT1, are vital in the uptake of synthetic nucleoside analogue drugs, used in cancer and viral chemotherapy. It is feasible that the efficacy of these drugs would be compromised in patients with the extremely rare AUGnull phenotype.

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GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

Cited by 15 publications

References 68 publications

GATA2 deficiency elevates interferon regulatory factor-8 to subvert a progenitor cell differentiation program

GATA2 deficiency elevates interferon regulatory factor-8 to subvert a progenitor cell differentiation program

RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis

Augustine Blood Group System and Equilibrative Nucleoside Transporter 1

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