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Single-cell analyses demonstrate that a heme-GATA1 feedback loop regulates red cell differentiation.

Authors
  • Doty, Raymond T1
  • Yan, Xiaowei2
  • Lausted, Christopher2
  • Munday, Adam D1
  • Yang, Zhantao1
  • Yi, Danielle2
  • Jabbari, Neda2
  • Liu, Li1
  • Keel, Siobán B1
  • Tian, Qiang2
  • Abkowitz, Janis L1
  • 1 Department of Medicine, Division of Hematology, University of Washington, Seattle, WA; and.
  • 2 Institute for Systems Biology, Seattle, WA.
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Jan 31, 2019
Volume
133
Issue
5
Pages
457–469
Identifiers
DOI: 10.1182/blood-2018-05-850412
PMID: 30530752
Source
Medline
Language
English
License
Unknown

Abstract

Erythropoiesis is the complex, dynamic, and tightly regulated process that generates all mature red blood cells. To understand this process, we mapped the developmental trajectories of progenitors from wild-type, erythropoietin-treated, and Flvcr1-deleted mice at single-cell resolution. Importantly, we linked the quantity of each cell's surface proteins to its total transcriptome, which is a novel method. Deletion of Flvcr1 results in high levels of intracellular heme, allowing us to identify heme-regulated circuitry. Our studies demonstrate that in early erythroid cells (CD71+Ter119neg-lo), heme increases ribosomal protein transcripts, suggesting that heme, in addition to upregulating globin transcription and translation, guarantees ample ribosomes for globin synthesis. In later erythroid cells (CD71+Ter119lo-hi), heme decreases GATA1, GATA1-target gene, and mitotic spindle gene expression. These changes occur quickly. For example, in confirmatory studies using human marrow erythroid cells, ribosomal protein transcripts and proteins increase, and GATA1 transcript and protein decrease, within 15 to 30 minutes of amplifying endogenous heme synthesis with aminolevulinic acid. Because GATA1 initiates heme synthesis, GATA1 and heme together direct red cell maturation, and heme stops GATA1 synthesis, our observations reveal a GATA1-heme autoregulatory loop and implicate GATA1 and heme as the comaster regulators of the normal erythroid differentiation program. In addition, as excessive heme could amplify ribosomal protein imbalance, prematurely lower GATA1, and impede mitosis, these data may help explain the ineffective (early termination of) erythropoiesis in Diamond Blackfan anemia and del(5q) myelodysplasia, disorders with excessive heme in colony-forming unit-erythroid/proerythroblasts, explain why these anemias are macrocytic, and show why children with GATA1 mutations have DBA-like clinical phenotypes. © 2019 by The American Society of Hematology.

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