The GATA factor revolution in hematology

Abstract

The discovery of the GATA binding protein (GATA factor) transcription factor family revolutionized hematology. Studies of GATA proteins have yielded vital contributions to our understanding of how hematopoietic stem and progenitor cells develop from precursors, how progenitors generate red blood cells, how hemoglobin synthesis is regulated, and the molecular underpinnings of nonmalignant and malignant hematologic disorders. This thrilling journey began with mechanistic studies on a β-globin enhancer- and promoter-binding factor, GATA-1, the founding member of the GATA family. This work ushered in the cloning of related proteins, GATA-2-6, with distinct and/or overlapping expression patterns. Herein, we discuss how the hematopoietic GATA factors (GATA-1-3) function via a battery of mechanistic permutations, which can be GATA factor subtype, cell type, and locus specific. Understanding this intriguing protein family requires consideration of how the mechanistic permutations are amalgamated into circuits to orchestrate processes of interest to the hematologist and more broadly.

Figure 1.

GATA-1 and GATA-2 protein attributes. (A) GATA-1 and GATA-2 protein attributes. N- and C-zinc fingers and posttranslational modification sites are indicated.^{,,, ,,,,,-} (B) Amino acid sequence alignment of human GATA-1 and GATA-2. Protein domains and posttranslational modification sites are highlighted.

Figure 2.

GATA factor mechanistic principles. (A) GATA switch model. GATA switches involve replacement of one GATA factor by another at a chromatin target site. GATA switches can be associated with an altered transcriptional output. The GATA switch is illustrated at the Gata2 locus. In erythroblasts, friend of GATA-1 (FOG-1) promotes GATA-1-mediated replacement of chromatin-bound GATA-2, instigating repression.^, (B) Coregulator dependency matrix model. “Sensitive” and “insensitive” denote whether reductions in the endogenous coregulators impact expression of the GATA-1 target genes. Distinct coregulator ensembles mediate GATA-1-dependent transcription in a locus-specific and context-dependent manner.^,,,

Figure 3.

Emerging GATA factor-dependent mechanistic circuits. (A) Ras-MAPK signaling controls GATA-2 activity. (B) GATA-2-GPR65 circuit negatively regulates hematopoiesis. (C) GATA-1-heme circuit regulates erythroid differentiation. (D) GATA-1-FoxO3-exosome circuit controls erythroid maturation.^, FFL, feed forward loop.

Figure 4.

GATA-2 mutations in human hematologic disorders inform GATA factor mechanisms. (A) Left, GATA-2 N-finger mutations in human AML patients with biallelic CEBPA mutations.^-,, V296 corresponds to GATA-1 V205, which enhances GATA-1 and FOG-1 binding. Right, C-finger mutations identified in AML-associated diseases.^-,,- T354M is a loss-of-function mutation that inhibits chromatin occupancy and target gene activation.^, L359V was identified in chronic myeloid leukemia. (B) Mutations at and near the +9.5 GATA switch site enhancer in pediatric MDS and MonoMAC syndrome.^,, del, deletion; ins, insertion.