Human diseases resulting from aberrant hemoglobin synthesis afflict large numbers of patients, and therapeutics for these disorders are far from optimal. Taken together with the merits of using the ?-globin locus as a model to understand cell type-specific transcriptional mechanisms, this problem has received considerable attention. Using innovative approaches, we identified factors and mechanisms controlling the adult ?-like globin genes. GATA-1 and its interactors function through dispersed sites at the ?-globin locus and loci encoding pivotal regulators of red cell biology, including heme biosynthetic enzymes. It is crucial to understand how factors select chromatin sites, recruit coregulators that modify/remodel chromatin, engage transcriptional machinery, and confer gene subnuclear localizations. Given powerful technologies, implicated factors, and unique expertise, we will address key issues to develop an integrative model to explain the transcriptional control of hemoglobin synthesis.
Specific Aim 1 - To test models to explain the relationship between mechanisms controlling globin genes and genes encoding heme biosynthetic enzymes. We hypothesize that GATA-1 functions with a unique cohort of trans-acting factors and coregulators to expel globin genes and the gene encoding a rate-limiting enzyme in heme biosynthesis, 4- aminolevulinic acid synthase (Alas2), from the nuclear periphery. This would establish a subnuclear positioning required for high-level transcription and coordinate globin chain production and heme synthesis. We will test models to explain how GATA-1-regulating factors initiate and/or maintain anchoring or repulsion of these loci at peripheral and internal sites.
Specific Aim 2 - To elucidate mechanisms underlying initiation and maintenance of GATA-1-dependent transcription. Nearly nothing is known about mechanisms that differentially initiate vs. maintain transcription, a problem particularly important for strategies to control transcription with a therapeutic outcome. We will use a powerful RNA interference asay to test the hypothesis that components regulating ?-globin and Alas2 transcription differ in their capacities to support initiation vs. maintenance.
Specific Aim 3 - To establish how GATA-1 mutations underlying human hematologic disorders dysregulate GATA factor-dependent genetic networks. Many questions remain unanswered regarding how disease mutations impair GATA-1 activity. We will determine how Arg216W and Arg216Gln mutations within the N-terminal zinc finger that underlie congenital erythropoietic porphyria, X- linked grey platelet syndrome, and thrombocytopenia with ?-thalassemia afect GATA-1 activity. These studies will yield broad insights into mechanisms controling hemoglobin synthesis, normal and malignant hematopoiesis, and additional developmental processes.
The proposed studies shall provide key insights into mechanisms underlying disorders of hemoglobin synthesis, including thalassemias, anemia, hematopoiesis, hematologic malignancies, and diseases associated with aberrant heme biosynthesis, including porphyrias. The work shall also develop conceptual frameworks for the design of novel therapeutic strategies for these human disorders.
| Peng, Yajing; Shapiro, Samantha L; Banduseela, Varuna C et al. (2018) Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging Cell 17:e12820 |
| Liu, Jinhua; Li, Yapu; Tong, Jingyuan et al. (2018) Long non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development. Nat Commun 9:4386 |
| Katsumura, Koichi R; Mehta, Charu; Hewitt, Kyle J et al. (2018) Human leukemia mutations corrupt but do not abrogate GATA-2 function. Proc Natl Acad Sci U S A 115:E10109-E10118 |
| Bresnick, Emery H; Hewitt, Kyle J; Mehta, Charu et al. (2018) Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond. Development 145: |
| McIver, Skye C; Hewitt, Kyle J; Gao, Xin et al. (2018) Dissecting Regulatory Mechanisms Using Mouse Fetal Liver-Derived Erythroid Cells. Methods Mol Biol 1698:67-89 |
| Tanimura, Nobuyuki; Liao, Ruiqi; Wilson, Gary M et al. (2018) GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism. Dev Cell 46:581-594.e4 |
| Mehta, Charu; Johnson, Kirby D; Gao, Xin et al. (2017) Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program. Cell Rep 20:2966-2979 |
| Hewitt, Kyle J; Katsumura, Koichi R; Matson, Daniel R et al. (2017) GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia. Dev Cell 42:213-225.e4 |
| Katsumura, Koichi R; Bresnick, Emery H; GATA Factor Mechanisms Group (2017) The GATA factor revolution in hematology. Blood 129:2092-2102 |
| Liu, Peng; Sanalkumar, Rajendran; Bresnick, Emery H et al. (2016) Integrative analysis with ChIP-seq advances the limits of transcript quantification from RNA-seq. Genome Res 26:1124-33 |
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