Histone H2A.X signaling and chromatin remodeling in late erythropoiesis

红细胞生成是一个巨大的过程，成年人平均产生约250万个红细胞

Erythropoiesis is a process of enormous magnitude, with the average adult producing approximately 2.5 million red blood cells each second. To maintain this impressive output, terminal erythroid maturation is coupled with rapid proliferation. In the span of 3-4 cell divisions, erythroid cells must condense their nuclei to approximately 1/10th of their original volume in anticipation of enucleation, which involves a dramatic compaction of the erythroid genome. Disruption this process is associated with myelodysplastic syndromes (MDS) and congenital anemias. The mechanisms involved, however, are poorly understood. Recent evidence from our group and others has implicated the variant histone H2A.X as an important component in normal erythroid maturation. Phosphorylation of this histone at S139 (γ-H2A.X) is an early feature of DNA repair pathways and contributes to the stability of broadly-distributed “foci” of DNA repair factors. Notably, we observe a burst of γ- H2A.X foci at a specific stage of erythroid maturation, concomitant with a significant increase in proliferation and replication rate, and with the final stages of nuclear condensation. Based on this and other observations, we hypothesize that histone H2A.X phosphorylation signals directly to downstream pathways that accomplish chromatin remodeling (through histone exchange) and compaction (through the induction of an apoptotic- related pathway). These studies will provide mechanistic insight into the still-opaque processes involved in terminal erythroid maturation, enhance our understanding of epigenetic gene regulation and chromatin compaction, and illuminate the basis for defects in erythropoiesis that can cause anemia.