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Review
. 2010 Oct 8;285(41):31087-93.
doi: 10.1074/jbc.R110.159079. Epub 2010 Jul 29.

GATA switches as developmental drivers

Affiliations
Review

GATA switches as developmental drivers

Emery H Bresnick et al. J Biol Chem. .

Abstract

Transcriptional networks orchestrate complex developmental processes. Such networks are commonly instigated by master regulators of development. Considerable progress has been made in elucidating GATA factor-dependent genetic networks that control blood cell development. GATA-2 is required for the genesis and/or function of hematopoietic stem cells, whereas GATA-1 drives the differentiation of hematopoietic progenitors into a subset of the blood cell lineages. GATA-1 directly represses Gata2 transcription, and this involves GATA-1-mediated displacement of GATA-2 from chromatin, a process termed a GATA switch. GATA switches occur at numerous loci with critical functions, indicating that they are widely utilized developmental control tools.

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Figures

FIGURE 1.
FIGURE 1.
GATA-1 directly represses the Gata2 locus during hematopoiesis. GATA-2 occupies multiple regulatory regions (GATA switch sites) at its own locus (71–73). Upon induction of GATA-1 expression, GATA-1 displaces GATA-2 (GATA switch), instigating transcriptional repression. Although the GATA switch is depicted to occur in the erythroid lineage, GATA-1 is also expressed in megakaryocytes, eosinophils, and mast cells, but mechanistic analyses of GATA switches are incomplete in these systems. CLP, common lymphoid progenitor; GMP, granulocyte-monocyte progenitor; BFU-E, burst-forming unit-erythroid; CFU-E, colony-forming unit-erythroid; CMP, common myeloid progenitor; MEP, megakaryocyte-erythroid progenitor; Pro Ery, proerythroblast; Poly, polychromatic normoblast; Ret, reticulocyte.
FIGURE 2.
FIGURE 2.
Functional attributes of GATA-1. Murine GATA-1 sequences within its N terminus are implicated in conferring transactivation. These sequences include the sumoylation site Lys137 (32), which facilitates GATA-1 activity in a context-dependent manner (33). Met83 represents an alternative translation start site that yields a leukemogenic GATA-1 protein in acute megakaryoblastic leukemia (87). As described in the text, the C-terminal finger mediates binding to GATA motifs, whereas the N-terminal finger stabilizes DNA binding and mediates sequence-specific DNA binding in certain contexts. The zinc fingers (ZnF) mediate multiple protein/protein interactions, with the FOG-1 interaction with the N-terminal finger being particularly critical. EKLF, erythroid Krüppel-like factor.
FIGURE 3.
FIGURE 3.
GATA switch model. In early-stage erythroblasts, GATA-2 and FOG-1 colocalize at chromatin sites, and upon elevation of GATA-1 levels as erythropoiesis proceeds, GATA-1 displaces GATA-2. FOG-1 facilitates GATA-1 occupancy and GATA switches, but in certain contexts, GATA-1 chromatin occupancy appears to be FOG-1-independent. As the GATA-1 N-terminal zinc finger can contact multiple FOG-1 zinc fingers (48, 49), we predict that GATA-1 enters the GATA-2·FOG-1 complex, creating a transient biochemical intermediate in which both GATA factors engage distinct FOG-1 zinc fingers simultaneously. Proteasome inhibitors stabilize GATA-2 and impair GATA switches (29), and therefore, the low stability of GATA-2 appears to ensure efficient GATA switches. However, whether the proteasome acts on chromatin-bound GATA-2 in unknown. An additional key aspect of the mechanism that requires additional study is to establish the precise precursor during hematopoiesis in vivo in which GATA-1 levels rise sufficiently to gain a competitive advantage over GATA-2 bound to chromatin target sites. Given the role of FOG-1 in promoting switches, presumably mechanisms that increase or decrease FOG-1 activity and/or alter FOG-1 levels control GATA switches, but this possibility has not yet been experimentally tested.

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