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Epo reprograms the epigenome of erythroid cells.

ABSTRACT: The hormone erythropoietin (Epo) is required for erythropoiesis, yet its molecular mechanism of action remains poorly understood, particularly with respect to chromatin dynamics. To investigate how Epo modulates the erythroid epigenome, we performed epigenetic profiling using an ex vivo murine cell system that undergoes synchronous erythroid maturation in response to Epo stimulation. Our findings define the repertoire of Epo-modulated enhancers, illuminating a new facet of Epo signaling. First, a large number of enhancers rapidly responded to Epo stimulation, revealing a cis-regulatory network of Epo-responsive enhancers. In contrast, most of the other identified enhancers remained in an active acetylated state during Epo signaling, suggesting that most erythroid enhancers are established at an earlier precursor stage. Second, we identified several hundred super-enhancers that were linked to key erythroid genes, such as Tal1, Bcl11a, and Mir144/451. Third, experimental and computational validation revealed that many predicted enhancer regions were occupied by TAL1 and enriched with DNA-binding motifs for GATA1, KLF1, TAL1/E-box, and STAT5. Additionally, many of these cis-regulatory regions were conserved evolutionarily and displayed correlated enhancer:promoter acetylation. Together, these findings define a cis-regulatory enhancer network for Epo signaling during erythropoiesis, and provide the framework for future studies involving the interplay of epigenetics and Epo signaling.

SUBMITTER: Perreault AA

PROVIDER: S-EPMC5551495 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Epo reprograms the epigenome of erythroid cells.

Perreault Andrea A AA Benton Mary Lauren ML Koury Mark J MJ Brandt Stephen J SJ Venters Bryan J BJ

Experimental hematology 20170412

The hormone erythropoietin (Epo) is required for erythropoiesis, yet its molecular mechanism of action remains poorly understood, particularly with respect to chromatin dynamics. To investigate how Epo modulates the erythroid epigenome, we performed epigenetic profiling using an ex vivo murine cell system that undergoes synchronous erythroid maturation in response to Epo stimulation. Our findings define the repertoire of Epo-modulated enhancers, illuminating a new facet of Epo signaling. First, ...[more]

PMID: 28410882

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Project description:We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade.

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Epo reprograms the epigenome of erythroid cells.

Publications

Epo reprograms the epigenome of erythroid cells.

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