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Histone H2A.X signaling and chromatin remodeling in late erythropoiesis

晚期红细胞生成过程中的组蛋白 H2A.X 信号传导和染色质重塑

基本信息

批准号：
10624464
负责人：
MICHAEL D BULGER
金额：
$ 30.26万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10624464
关键词：
Acinus organ component Address Adult Anemia Aplastic Anemia Apoptosis Apoptotic Basophilic Erythroblast Biological Models Bone Marrow CASP3 gene CASP9 gene Cell Cycle Cell Line Cell Nucleus Cell division Cell physiology Chromatin Complex Congenital Anemia Coupled DNA Damage DNA Repair DNA Repair Pathway DNA biosynthesis Data Defect Deposition Development Direct Costs Dysmyelopoietic Syndromes Epigenetic Process Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Excision Exhibits Gene Expression Gene Expression Regulation Genome Genomic DNA Genomics Goals Hematology Hemoglobin Higher Order Chromatin Structure Histone H2A Histones Induction of Apoptosis Knock-out Knockout Mice Light Mediating Molecular Chaperones Mus Mutation Non-Malignant Nuclear Output Pathway interactions Pattern Phosphorylation Physical condensation Preparation Process Proliferating Research Role Serine Signal Transduction Site Tail Testing United States National Institutes of Health Variant chromatin remodeling design gene repression gene synthesis genetic variant genome editing insight progenitor programs protein protein interaction recruit repaired response stem cells

项目摘要

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.

红细胞生成是一个巨大的过程，平均每个成年人产生大约250万每秒钟的红细胞数量。为了保持这一令人印象深刻的产量，末期红系成熟与迅速扩散。在3-4次细胞分裂的过程中，红系细胞必须将其细胞核浓缩到大约 1/10的原始体积，这涉及到戏剧性的压缩红系基因组。这一过程与骨髓增生异常综合征(MDS)和先天性贫血。然而，人们对其中涉及的机制知之甚少。最近的证据来自我们的 Group和其他人已经将变异组蛋白H_2A.X作为正常红系的重要组成部分成熟。这个组蛋白在S139(γ-H_2A.X)的磷酸化是DNA修复途径和有助于DNA修复因子广泛分布的“焦点”的稳定性。值得注意的是，我们观察到γ- 红系成熟特定阶段的H_2A.X灶，伴随着显著的增殖增加和复制速度，并与核凝结的最后阶段。基于这一点和其他观察，我们假设组蛋白H_2A.X的磷酸化信号直接传递到下游通路，从而完成染色质重塑(通过组蛋白交换)和致密化(通过诱导细胞凋亡- 相关途径)。这些研究将提供对仍不透明的过程的机械性洞察红系终末成熟，增强我们对表观遗传基因调控和染色质的理解致密性，并阐明了导致贫血的红细胞生成缺陷的基础。