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Dev Cell. 2017 Aug 7;42(3):213-225.e4. doi: 10.1016/j.devcel.2017.07.009.

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

Author information

1
Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
2
Department of Chemistry, UW-Madison, Madison, WI, USA.
3
Department of Chemistry, UW-Madison, Madison, WI, USA; Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
4
Center for Genome Engineering, Institute for Basic Science and Department of Chemistry, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul, South Korea.
5
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
6
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
7
Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Electronic address: ehbresni@wisc.edu.

Abstract

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.

KEYWORDS:

GATA-2; anemia; enhancer; erythroid; hematopoiesis; regeneration

PMID:
28787589
PMCID:
PMC5578808
DOI:
10.1016/j.devcel.2017.07.009
[Indexed for MEDLINE]
Free PMC Article

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