From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications

Abstract

This article reviews the regulation of production of RBCs at several levels. We focus on the regulated expansion of burst-forming unit-erythroid erythroid progenitors by glucocorticoids and other factors that occur during chronic anemia, inflammation, and other conditions of stress. We also highlight the rapid production of RBCs by the coordinated regulation of terminal proliferation and differentiation of committed erythroid colony-forming unit-erythroid progenitors by external signals, such as erythropoietin and adhesion to a fibronectin matrix. We discuss the complex intracellular networks of coordinated gene regulation by transcription factors, chromatin modifiers, and miRNAs that regulate the different stages of erythropoiesis.

Figure 1

An overview of erythropoiesis: regulation at multiple levels by multiple proteins and miRNAs. Formation of RBCs from HSCs is regulated by signaling through both external factors (blue), such as cytokines and fibronectin, as well as intracellular factors, such as transcription factors (black) and miRNAs (red). Below the differentiation network, a timeline and images are shown for in vitro methylcellulose colony formation of murine BFU-E and CFU-E.

Figure 2

Transcription factors, Pol II status, and histone modifications associated with actively transcribed and repressed genes in erythroid cells. For genes activated during differentiation (bottom panel), the GATA-1 activation-associated proteins exist in different complexes (as indicated by the double arrows) through binding to both distal regulatory regions and promoter regions near the TSS. H3K4me2 and H3K4me3 are enriched in some of these bound regions. TIF-1 and the SCL complex recruit pTEF-b to promote Pol II elongation by phosphorylating DSIF, NELF, and Pol II. SCF could be the link between the GATA-1 complex and Pol II elongation machinery. H3K79me2 and H3K36me3 are often enriched in the transcribed portion of the gene. Among repressed genes (top panel), the GATA-1 repressor complexes are less clear and could exist in different forms as indicated by the double arrows. H3K27me3 is enriched near the TSS. Pol II is either not bound or is paused around the TSS. In the absence of TIF-1, recruitment of p-TEFb is impaired, and DSIF and NELF inhibit the phosphorylation of Pol II and Pol II elongation.

Figure 3

BFU-E self-renewal: The probability of erythroid progenitor self-renewal versus differentiation depends on extrinsic and intrinsic factors. BFU-E progenitors either self-renew or differentiate depending on the body's need for generation of CFU-E and Epo-dependent erythroblasts. Although BFU-E self-renewal is very limited during steady-state erythropoiesis in the bone marrow, it is virtually limitless in the spleen during conditions of stress erythropoiesis. The cytokines Scf, Bmp4, and Shh promote self-renewal in addition, as does stimulation by GCs and hypoxia. These signals activate transcription factors Myc, Smad5, Scl, Gata2, Myb, and Hif1a.