GATA Factor Mechanisms in Erythroid Regeneration

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ABSTRACT Erythropoiesis, the production of red blood cells (RBCs), is fine-tuned to meet physiological demands. During regeneration or “stress erythropoiesis” caused by anemia, a subset of genes and proteins are upregulated in association with an increased rate of RBC production. A critical gap in understanding erythroid regeneration hinges on whether the activation of gene regulatory networks in erythroid progenitors (driven by transcription factors) are stress-specific or represent broader control mechanisms in other contexts. Moreover, the underlying etiologies in which the erythroid system loses its ability to regenerate in chronic anemias are often unclear. We discovered that the Sterile Alpha Motif Domain-14 (Samd14) gene is elevated in models of acute/chronic anemia. Samd14 is regulated by the transcription factor GATA2, which coordinates a network of genes with critical functions in hematopoiesis and hematologic disease. The GATA2-occupied Samd14 cis-element (Samd14-Enh) is required for survival in a model of hemolytic anemia, but dispensable for steady state erythropoiesis. Erythroid progenitors lacking Samd14-Enh have impaired c-Kit signaling, a quintessential pathway regulating hematopoiesis and erythropoiesis. These results reveal the involvement of a GATA2-Samd14-c-Kit regulatory axis in erythroid regeneration. Whereas SAM domain-containing proteins are involved in hematopoiesis and cell signaling, and several are upregulated in anemia, their mechanisms of action are not well understood. Our data suggests additional cohorts of enhancers with properties mimicking the Samd14-Enh are anemia-regulated. We hypothesize that Samd14 and additional GATA2 and Regeneration-Activated (G2R) enhancers control erythroid regeneration. In Aim 1, mechanistic analyses in human and mouse will define Samd14 requirements for cell signaling and survival of erythroid progenitors. Aim 2 will delineate a GATA2 and anemia-regulated (G2R) gene network governing a sector of the complex biology surrounding anemia responses. Approaches using primary human/mouse cells and innovative mouse genetic model approaches will test SAMD14 mechanisms (and other SAM domain proteins) in c-Kit signaling and erythroid regeneration. These aims will establish valuable contrasts between homeostatic and regenerative erythropoietic mechanisms, enhancer knockout and gene knockout phenotypes, and between functionally-distinct cis-elements which contain similar sequence and molecular properties. By elucidating a GATA2-Samd14-c-Kit axis in acute anemia, and global/locus-specific GATA2 mechanisms of Samd14-Enh-like cis-elements, we expect these studies will reveal fundamental gene regulatory mechanisms in erythroid regeneration with implications in hematologic disease, including anemias.