Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis

Mol Cell Biol. 2017 Mar 31;37(8):e00592-16. doi: 10.1128/MCB.00592-16. Print 2017 Apr 15.


GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of the Gata1 gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of the Gata1 gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring a Gata1 bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressed Gata2 transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion of Dnmt1 in HSPCs activated Gata1 expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation.

Keywords: Gata1 gene regulation; erythropoiesis; hematopoietic stem and progenitor cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / genetics*
  • Cell Lineage
  • Colony-Forming Units Assay
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / genetics*
  • Embryo, Mammalian / metabolism
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism
  • Erythropoiesis / genetics*
  • GATA1 Transcription Factor / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Haploidy
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Homeostasis / genetics
  • Integrases / metabolism
  • Liver / embryology
  • Liver / metabolism
  • Mice, Transgenic
  • Models, Biological
  • Survival Analysis


  • GATA1 Transcription Factor
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • Dnmt1 protein, mouse
  • Cre recombinase
  • Integrases