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.
|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|
|Gao, Xin; Wu, Tongyu; Johnson, Kirby D et al. (2016) GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis. Stem Cell Reports 6:368-82|
|Tanimura, Nobuyuki; Miller, Eli; Igarashi, Kazuhiko et al. (2016) Mechanism governing heme synthesis reveals a GATA factor/heme circuit that controls differentiation. EMBO Rep 17:249-65|
|McIver, Skye C; Katsumura, Koichi R; Davids, Elsa et al. (2016) Exosome complex orchestrates developmental signaling to balance proliferation and differentiation during erythropoiesis. Elife 5:|
|Johnson, Kirby D; Kong, Guangyao; Gao, Xin et al. (2015) Cis-regulatory mechanisms governing stem and progenitor cell transitions. Sci Adv 1:e1500503|
|Hewitt, Kyle J; Kim, Duk Hyoung; Devadas, Prithvia et al. (2015) Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome. Mol Cell 59:62-74|
|DeVilbiss, Andrew W; Sanalkumar, Rajendran; Hall, Bryan D R et al. (2015) Epigenetic Determinants of Erythropoiesis: Role of the Histone Methyltransferase SetD8 in Promoting Erythroid Cell Maturation and Survival. Mol Cell Biol 35:2073-87|
|Yamazaki, Hiromi; Suzuki, Mikiko; Otsuki, Akihito et al. (2014) A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell 25:415-27|
|Katsumura, Koichi R; Yang, Chenxi; Boyer, Meghan E et al. (2014) Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2. EMBO Rep 15:938-47|
|DeVilbiss, Andrew W; Sanalkumar, Rajendran; Johnson, Kirby D et al. (2014) Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points. Exp Hematol 42:618-29|
Showing the most recent 10 out of 35 publications