Deletion of the Scl+19 enhancer increases the blood stem cell compartment without affecting the formation of mature blood lineages

Dominik Spensberger, Ekaterini Kotsopoulou, Rita Ferreira, Cyril Broccardo, Linda M. Scott, Nasios Fourouclas, Katrin Ottersbach, Anthony R. Green, Berthold Goettgens*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The stem cell leukemia (Scl)/Tal1 gene is essential for normal blood and endothelial development, and is expressed in hematopoietic stem cells (HSCs), progenitors, erythroid, megakaryocytic, and mast cells. The Scl +19 enhancer is active in HSCs and progenitor cells, megakaryocytes, and mast cells, but not mature erythroid cells. Here we demonstrate that in vivo deletion of the Scl +19 enhancer (Scl(Delta 19/Delta 19)) results in viable mice with normal Scl expression in mature hematopoietic lineages. By contrast, Scl expression is reduced in the stem/progenitor compartment and flow cytometry analysis revealed that the HSC and megakaryocyte-erythroid progenitor populations are enlarged in Scl(Delta 19/Delta 19) mice. The increase in HSC numbers contributed to enhanced expansion in bone marrow transplantation assays, but did not affect multilineage repopulation or stress responses. These results affirm that the Set +19 enhancer plays a key role in the development of hematopoietic stem/progenitor cells, but is not necessary for mature hematopoietic lineages. Moreover, active histone marks across the Set locus were significantly reduced in Scl(Delta 19/Delta 19) fetal liver cells without major changes in steady-state messenger RNA levels, suggesting post-transcriptional compensation for loss of a regulatory element, a result that might be widely relevant given the frequent observation of mild phenotypes after deletion of regulatory elements. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

Original languageEnglish
Pages (from-to)588-598
Number of pages11
JournalExperimental Hematology
Volume40
Issue number7
DOIs
Publication statusPublished - Jul 2012

Keywords

  • GENOME-WIDE ANALYSIS
  • TRANSCRIPTION FACTOR
  • HEMATOPOIETIC PROGENITORS
  • TARGETED DELETION
  • ENDOTHELIAL-CELLS
  • MICE LACKING
  • IN-VIVO
  • GENE
  • ADULT
  • EXPRESSION

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