Epigenetic and Transcriptional Control of Erythropoiesis

Abstract

Erythropoiesis is a process of enormous magnitude, with the average person generating two to three million red cells every second. Erythroid progenitors start as large cells with large nuclei, and over the course of three to four cell divisions they undergo a dramatic decrease in cell size accompanied by profound nuclear condensation, which culminates in enucleation. As maturing erythroblasts are undergoing these dramatic phenotypic changes, they accumulate hemoglobin and express high levels of other erythroid-specific genes, while silencing much of the non-erythroid transcriptome. These phenotypic and gene expression changes are associated with distinct changes in the chromatin landscape, and require close coordination between transcription factors and epigenetic regulators, as well as precise regulation of RNA polymerase II activity. Disruption of these processes are associated with inherited anemias and myelodysplastic syndromes. Here, we review the epigenetic mechanisms that govern terminal erythroid maturation, and their role in human disease.

Genetic Modulation of the Erythrocyte Phenotype Associated with Retinopathy of Prematurity—A Multicenter Portuguese Cohort Study

“…Epigenetic factors drive the differentiation of red blood cells. During erythroid maturation, changes in histones have been implicated in the regulation of nuclear condensation and gene expression [51,52]. KDM1A, a lysine-specific histone demethylase, plays a key role in erythroid maturation, erythroid gene regulation, and HbF silencing [52,53].…”

“…KDM1A plays a critical role in the regulation of erythroid gene and erythroid maturation [52]. KDM1A knockdown in mice or deletion of KDM1A in hematopoietic stem cells results in anemia and reduction in mature blood cells [53].…”

Physiological functions of mitophagy

“…Indeed, basal mitophagy levels are, for example, enhanced during the elimination of sperm-derived mitochondria after fertilization of the egg, erythrocyte development, perinatal cardiac metabolic maturation, and retinal ganglion cell (RGC) differentiation in mammals. During erythropoiesis, colony-forming unit erythroid cells need to undergo a series of programmed processes that lead to the formation of mature enucleated and organelle-free red blood cells [34]. The reason these cells need to lose mitochondria is clear: to increase oxygen storage, by minimizing oxygen consumption by the organelle and maximizing space for hemoglobin.…”

The miR-144/Hmgn2 regulatory axis orchestrates chromatin organization during erythropoiesis

“…These rearrangements in nuclear organization are needed to restrict cellular fate to the erythroid lineage and direct cellular machinery toward the synthesis of proteins necessary for the proper function of erythrocytes 22 , 23 . Perturbations of erythrocyte maturation can lead to anemia and myelodysplastic syndromes 24 , 25 .…”