GATA1 Mutation in Defective Erythropoiesis

  • Crispino, John D (PD/PI)

Project: Research project

Project Details


GATA1 is a transcription factor that is required for survival and maturation of erythroid cells. In the absence of GATA1, mouse embryos die from anemia in mid-gestation. In humans, GATA1 mutations are associated with a spectrum of blood disorders, including congenital dyserythropoietic anemia and thrombocytopenia, porphyria, and Diamond-Blackfan Anemia (DBA). In the presence of trisomy 21, GATA1 mutations that delete the Nterminus lead to Down syndrome associated Acute Megakaryoblastic Leukemia (DS-AMKL). We recently demonstrated that a GATA1 mutant, which fails to bind FOG1 and is associated with rare cases of cases of dyserythropoietic anemia, fails to bind chromatin in the same manner as wild-type GATA1. This differential chromatin binding allows GATA1 to promote mast cell formation instead of red cell or megakaryocyte development. In a similar fashion, we have recently discovered that GATA1 molecules that lack the N-terminal activation domain, seen in both DBA and DS-AMKL, also fail to bind chromatin in the same way as full-length GATA1. Of interest, genes that are not properly bound or regulated by GATA1s include critical red cell genes such as Alas2, Slc4a1, and Klf1 (EKLF). In this grant, we will precisely define the requirement for the Nterminus of GATA1 in red cell development. Our aim is to discover how the GATA1 mutations that lead to expression of GATA1s in place of the full-length protein cause defects in the erythroid lineage and congenital anemia, including DBA. Our overarching hypothesis is that the reduced chromatin binding and aberrant gene regulation by GATA1s leads to impaired specification and terminal differentiation of red blood cells. Our aims are to: 1) Correlate chromatin occupancy of GATA1s with gene expression defects in primary GATA1s knock-in erythroid progenitor cells to identify key direct target genes that are dysregulated; 2) Investigate the consequences of the GATA1s mutation on erythroid specification and differentiation; and 3) Determine if loss of the N-terminus reduces the interaction with essential cofactors and in turn affects their chromatin occupancy. The research described in this proposal will greatly expand our insights into how loss of the N-terminus of GATA1 alters erythropoiesis and will benefit patients with congenital anemia and DS-AMKL.
Effective start/end date9/18/137/31/16


  • National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK101329)


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