Histone H2A.X signaling and chromatin remodeling in late erythropoiesis

红细胞生成是一个巨大的过程，成人平均产生约250万个红细胞。 每秒钟都有红血球为了维持这一令人印象深刻的输出，终末红细胞成熟与 快速扩散。在3-4次细胞分裂的跨度中，红系细胞必须将它们的核浓缩到大约1000 μ m。 1/10的原始体积，预期摘除，这涉及到一个戏剧性的压缩， 红细胞基因组破坏这一过程与骨髓增生异常综合征（MDS）有关， 先天性贫血然而，对所涉及的机制知之甚少。我们最近的证据显示， 组和其他人已经暗示变异组蛋白H2A.X是正常红细胞系中的重要组分 成熟这种组蛋白在S139（γ-H2A.X）处的磷酸化是DNA修复途径的早期特征， 有助于DNA修复因子广泛分布的“病灶”的稳定性。值得注意的是，我们观察到γ- H2A.X病灶在红系成熟的特定阶段，伴随着增殖的显著增加 和复制率，以及核凝聚的最后阶段。根据这一点和其他观察， 我们假设组蛋白H2A.X磷酸化直接向下游通路发出信号， 染色质重塑（通过组蛋白交换）和致密化（通过诱导凋亡， 相关路径）。这些研究将提供机制的洞察力，仍然不透明的过程中涉及 终末红系成熟，增强我们对表观遗传基因调控和染色质的理解 压实，并阐明了红细胞生成缺陷的基础，可导致贫血。

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.