What type of study is this?

This is a Animal Study study (also classified as: In Vitro Study).

What question did this study set out to answer?

To investigate the genomic regulation of erythroferrone expression during erythropoiesis.

December 8, 2025Open Access

Expression of the erythroid controller of systemic iron homeostasis erythroferrone is cis-regulated

RSRobert SertoriFox Chase Cancer Center MPMartin PálCharles Sturt University APAnne PettikiriarachchiWalter and Eliza Hall Institute of Medical Research

Key Points

To investigate the genomic regulation of erythroferrone expression during erythropoiesis.
Characterized ERFE expression using a human erythroblast model (HUDEP-2)
Applied ATAC-Seq to study chromatin accessibility during erythroid differentiation
Conducted CUT&RUN experiments to analyze transcription factor binding patterns
Performed chromosome conformation capture (Capture-C) to identify enhancer-promoter interactions
Utilized CRISPR-Cas9 to investigate the functional relevance of specific genomic regions.
ERFE mRNA expression increased during erythroblast differentiation
Identified accessible chromatin around the ERFE locus in late-stage erythroblasts
GATA1, KLF1 and TAL1 transcription factors bind to regulatory regions
ERFE knockout lines showed reduced ERFE expression compared to controls

Abstract

Abstract Erythroferrone (ERFE) is secreted from erythroblasts in response to increased erythropoiesis to suppress hepcidin, enabling enhanced nutritional iron absorption and iron release from the reticuloendothelial system, facilitating iron availability to the bone marrow and hence haemoglobin and thus red cell production1. In erythropoietic disorders such as thalassaemia, ineffective erythropoiesis results in erythroferrone upregulation, chronic hepcidin suppression and iron overload2. Despite the critical role of erythroferrone in systemic iron homeostasis and an emerging role as a therapeutic target, the molecular regulation of ERFE expression has not been described. Here, we sought to characterize the genomic regulation of ERFE using a human erythroblast model. We leveraged a well-characterized conditionally immortalized EPO-dependent human erythroid progenitor cell model (HUDEP-2) and conducted in vitro erythroid differentiation to generate late-stage orthochromatic erythroblasts. First, we confirmed that ERFE mRNA expression is increased at the intermediate stage of erythroblast differentiation in human-derived cells, consistent with previous animal data1. Next, we deployed ATAC-Seq and CUT46(7):678-684. 2. Kautz L, Jung G, Du X, et al. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood. 2015;126(17):2031-2037.

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