Gfi1–cells and circuits: unraveling transcriptional networks of development and disease

Section: Introductionmentioning

confidence: 99%

Gfi-1 regulates the erythroid transcription factor network through Id2 repression in murine hematopoietic progenitor cells

Kim

Klarmann

Keller

2014

“…Through a precisely controlled and perpetual process of self-renewal, proliferation, and differentiation, all of the hematopoietic lineages develop from HSCs. [16][17][18][19] Transcription factors play a major role during hematopoiesis and represent a very distinct layer of regulation, and the zinc finger proteins Gfi1 and Gfi1b exemplify such regulatory factors [20][21][22][23][24] ( Figure 1A). The generation of mice transgenic for Gfi1 and Gfi1b promoter sequences linked to reporter genes has made it possible to analyze the expression patterns of both genes during hematopoiesis 25,26 ( Figure 2).…”

Section: Expression Of Gfi1 and Gfi1b During Normal Hematopoiesismentioning

confidence: 99%

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

Möröy

Vaßen

Wilkes

et al. 2015

The DNA-binding zinc finger transcription factors Gfi1 and Gfi1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of Gfi1 and Gfi1b reporter mice made it possible to visualize their cell type–specific expression and to understand their function in hematopoietic lineages. We now know that Gfi1 is primarily important in myeloid and lymphoid differentiation, whereas Gfi1b is crucial for the generation of red blood cells and platelets. Several rare hematologic diseases are associated with acquired or inheritable mutations in the GFI1 and GFI1B genes. Certain patients with severe congenital neutropenia carry mutations in the GFI1 gene that lead to the disruption of the C-terminal zinc finger domains. Other mutations have been found in the GFI1B gene in families with inherited bleeding disorders. In addition, the Gfi1 locus is frequently found to be a proviral integration site in retrovirus-induced lymphomagenesis, and new, emerging data suggest a role of Gfi1 in human leukemia and lymphoma, underlining the role of both factors not only in normal hematopoiesis, but also in a wide spectrum of human blood diseases.

“…[36][37][38] Mice embryos lacking Gfi1b die in utero of anemia caused by defective erythroblast maturation and they also harbor developmentally arrested MEGs, 39 similar to the phenotype caused by loss of GATA1. GFI1B regulates proliferation and differentiation of MEPs through effects on transforming growth factorb signaling.…”

Section: Gfi1bmentioning

confidence: 99%

Erythro-megakaryocytic transcription factors associated with hereditary anemia

Crispino

Weiss

2014

Most heritable anemias are caused by mutations in genes encoding globins, red blood cell (RBC) membrane proteins, or enzymes in the glycolytic and hexose monophosphate shunt pathways. A less common class of genetic anemia is caused by mutations that alter the functions of erythroid transcription factors (TFs). Many TF mutations associated with heritable anemia cause truncations or amino acid substitutions, resulting in the production of functionally altered proteins. Characterization of these mutant proteins has provided insights into mechanisms of gene expression, hematopoietic development, and human disease. Mutations within promoter or enhancer regions that disrupt TF binding to essential erythroid genes also cause anemia and heritable variations in RBC traits, such as fetal hemoglobin content. Defining the latter may have important clinical implications for de-repressing fetal hemoglobin synthesis to treat sickle cell anemia and β thalassemia. Functionally important alterations in genes encoding TFs or their cognate cis elements are likely to occur more frequently than currently appreciated, a hypothesis that will soon be tested through ongoing genome-wide association studies and the rapidly expanding use of global genome sequencing for human diagnostics. Findings obtained through such studies of RBCs and associated diseases are likely generalizable to many human diseases and quantitative traits.