Constructing and deconstructing GATA2-regulated cell fate programs to establish developmental trajectories

Johnson, Kirby D.; Conn, Daniel; Shishkova, Evgenia; Katsumura, Koichi R.; Liu, Peng; Shen, Siqi; Ranheim, Erik A.; Kraus, Sean G.; Wang, Weixin; Calvo, Katherine R.; Hsu, Amy P.; Holland, Steven M.; Coon, Joshua J.; Keleş, Sündüz; Bresnick, Emery H.

doi:10.1084/jem.20191526

Cited by 31 publications

(90 citation statements)

References 101 publications

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“…Quantification of RNA and protein expression with -77 +/+ or -77 -/- HSPCs isolated from E14.5 fetal livers revealed a significant reduction (68 ± 12%; p = 0.39) in Slc29a1 mRNA in -77 -/- vs. -77 +/+ cells ( Fig 9A ). As expected [ 30 , 32 ], Gata2 mRNA was significantly lower in -77 -/- vs. -77 +/+ cells (87 ± 8.4%; p = 0.0026) ( Fig 9A ). To determine if GATA2 regulates Slc29a1 protein levels, we conducted semi-quantitative Western blotting in -77 +/+ and -77 -/- E14.5 fetal liver-derived HSPCs.…”

Section: Resultssupporting

confidence: 85%

“…-77 +/+ cells (Fig 9A). As expected [30,32], Gata2 mRNA was significantly lower in -77 -/vs. -77 +/+ cells (87 ± 8.4%; p = 0.0026) ( Fig 9A).…”

Section: Adenosine Circuit Embedded Within Gata Factor-regulated Genesupporting

confidence: 80%

“…GATA2 functions through the Gata2 –77 enhancer (-77) to confer Gata2 transcription in myelo-erythroid progenitor [ 30 ] and erythroid precursor cells [ 31 ]. In these cells, -77 enhancer deletion reduces Gata2 expression and protein levels ~80%, and GATA2 re-expression rescues molecular/cellular phenotypes [ 30 , 32 ]. To determine if GATA2 regulates an SLC gene cohort resembling or distinct from the GATA1-regulated cohort, we used our RNA-seq dataset that analyzed differentially expressed genes in Gata2 –77 +/+ vs. -77 -/- primary murine fetal liver erythroid precursor cells [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

“…Intracellular adenosine accumulation, e.g. in adenosine kinase deficiency, results in elevated s-adenosylhomocysteine, which inhibits s-adenosylmethionine (SAM)-dependent transmethylation reactions [ 32 ]. Since SAM is a requisite cofactor for DNA, RNA and protein methylation reactions that underlie epigenetic control of gene expression [ 56 , 57 ], mechanisms governing adenosine homeostasis impact genome function.…”

Section: Discussionmentioning

confidence: 99%

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

Zwifelhofer

Cai²,

Liao

et al. 2020

PLoS Genet

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Developmental-regulatory networks often include large gene families encoding mechanistically-related proteins like G-protein-coupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters. In principle, a common mechanism may confer expression of multiple members integral to a developmental process, or diverse mechanisms may be deployed. Using genetic complementation and enhancer-mutant systems, we analyzed the 456 member SLC family that establishes the small molecule constitution of cells. This analysis identified SLC gene cohorts regulated by GATA1 and/or GATA2 during erythroid differentiation. As >50 SLC genes shared GATA factor regulation, a common mechanism established multiple members of this family. These genes included Slc29a1 encoding an equilibrative nucleoside transporter (Slc29a1/ENT1) that utilizes adenosine as a preferred substrate. Slc29a1 promoted erythroblast survival and differentiation ex vivo. Targeted ablation of murine Slc29a1 in erythroblasts attenuated erythropoiesis and erythrocyte regeneration in response to acute anemia. Our results reveal a GATA factor-regulated SLC ensemble, with a nucleoside transporter component that promotes erythropoiesis and prevents anemia, and establish a mechanistic link between GATA factor and adenosine mechanisms. We propose that integration of the GATA factor-adenosine circuit with other components of the GATA factor-regulated SLC ensemble establishes the small molecule repertoire required for progenitor cells to efficiently generate erythrocytes.

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Section: Resultssupporting

confidence: 85%

“…-77 +/+ cells (Fig 9A). As expected [30,32], Gata2 mRNA was significantly lower in -77 -/vs. -77 +/+ cells (87 ± 8.4%; p = 0.0026) ( Fig 9A).…”

Section: Adenosine Circuit Embedded Within Gata Factor-regulated Genesupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Zwifelhofer

Cai²,

Liao

et al. 2020

PLoS Genet

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“…GATA2 is a master transcriptional regulator of hematopoiesis (Tsai et al 1994;Katsumura et al 2017). The +9.5 Gata2 enhancer triggers HSC generation in the AGM (Gao et al 2013;Soukup et al 2019), and both the +9.5 and -77 enhancers confer differentiation potential to myelo-erythroid progenitor cells (Mehta et al 2017;Johnson et al 2020). In addition to the three datasets, we analyzed wild type vs. Exosc10 mutant pluripotent embryonic stem cells (Pefanis et al 2015).…”

Section: New Transcripts Were Discovered By Pram From Mouse Hematopoimentioning

confidence: 99%

PRAM: a novel pooling approach for discovering intergenic transcripts from large-scale RNA sequencing experiments

et al. 2020

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Publicly available RNA-seq data is routinely used for retrospective analysis to elucidate new biology. Novel transcript discovery enabled by joint analysis of large collections of RNA-seq datasets has emerged as one such analysis. Current methods for transcript discovery rely on a '2-Step' approach where the first step encompasses building transcripts from individual datasets, followed by the second step that merges predicted transcripts across datasets. To increase the power of transcript discovery from large collections of RNA-seq datasets, we developed a novel '1-Step' approach named Pooling RNA-seq and Assembling Models (PRAM) that builds transcript models from pooled RNA-seq datasets. We demonstrate in a computational benchmark that '1-Step' outperforms '2-Step' approaches in predicting overall transcript structures and individual splice junctions, while performing competitively in detecting exonic nucleotides. Applying PRAM to 30 human ENCODE RNA-seq datasets identified unannotated transcripts with epigenetic and RAMPAGE signatures similar to those of recently annotated transcripts. In a case study, we discovered and experimentally validated new transcripts through the application of PRAM to mouse hematopoietic RNA-seq datasets. We uncovered new transcripts that share a differential expression pattern with a neighboring gene Pik3cg implicated in human hematopoietic phenotypes, and we provided evidence for the conservation of this relationship in human. PRAM is implemented as an R/Bioconductor package.

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GATA2 deficiency syndrome: A decade of discovery

et al. 2021

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GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms, of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 480 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 240 of these confirmed to be familial and 24 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0–78 years) and myelodysplastic syndrome is the first diagnosis in 75% of these cases with acute myeloid leukemia in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss‐of‐function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing, and expression. In this review, we provide the first expert‐curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings.

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Constructing and deconstructing GATA2-regulated cell fate programs to establish developmental trajectories

Cited by 31 publications

References 101 publications

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

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

PRAM: a novel pooling approach for discovering intergenic transcripts from large-scale RNA sequencing experiments

GATA2 deficiency syndrome: A decade of discovery

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