GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia

Publication date: 7 August 2017
Source:Developmental Cell, Volume 42, Issue 3
Author(s): Kyle J. Hewitt, Koichi R. Katsumura, Daniel R. Matson, Prithvia Devadas, Nobuyuki Tanimura, Alexander S. Hebert, Joshua J. Coon, Jin-Soo Kim, Colin N. Dewey, Sunduz Keles, Siyang Hao, Robert F. Paulson, Emery H. Bresnick
An enhancer with amalgamated E-box and GATA motifs (+9.5) controls expression of the regulator of hematopoiesis GATA-2. While similar GATA-2-occupied elements are common in the genome, occupancy does not predict function, and GATA-2-dependent genetic networks are incompletely defined. A "+9.5-like" element resides in an intron of Samd14 (Samd14-Enh) encoding a sterile alpha motif (SAM) domain protein. Deletion of Samd14-Enh in mice strongly decreased Samd14 expression in bone marrow and spleen. Although steady-state hematopoiesis was normal, Samd14-Enh^−/− mice died in response to severe anemia. Samd14-Enh stimulated stem cell factor/c-Kit signaling, which promotes erythrocyte regeneration. Anemia activated Samd14-Enh by inducing enhancer components and enhancer chromatin accessibility. Thus, a GATA-2/anemia-regulated enhancer controls expression of an SAM domain protein that confers survival in anemia. We propose that Samd14-Enh and an ensemble of anemia-responsive enhancers are essential for erythrocyte regeneration in stress erythropoiesis, a vital process in pathologies, including β-thalassemia, myelodysplastic syndrome, and viral infection.

Graphical abstract

Teaser

GATA-2 is a regulator of hematopoiesis. Hewitt et al. find that a GATA-2-regulated enhancer, controlling expression of an SAM domain protein, promotes red blood cell regeneration and hence survival of anemia in mice. This enhancer is part of a family of anemia-responsive elements, which may orchestrate the response to anemia.


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