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

TitleDeletion of the Scl +19 enhancer increases the blood stem cell compartment without affecting the formation of mature blood lineages.
Publication TypeJournal Article
Year of Publication2012
AuthorsSpensberger D, Kotsopoulou E, Ferreira R, Broccardo C, Scott LM, Fourouclas N, Ottersbach K, Green AR, Göttgens B
JournalExp Hematol
Date Published2012 Jul
KeywordsAnimals, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Enhancer Elements, Genetic, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Mice, Mice, Mutant Strains, Proto-Oncogene Proteins, Sequence Deletion, Stress, Physiological

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(Δ19/Δ19)) 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(Δ19/Δ19) 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 Scl +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 Scl locus were significantly reduced in Scl(Δ19/Δ19) 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.

Alternate JournalExp. Hematol.
PubMed ID22401818
PubMed Central IDPMC3387379
Grant List079249 / / Wellcome Trust / United Kingdom
G0800784 / / Medical Research Council / United Kingdom
/ / Cancer Research UK / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
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