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.

红细胞生成是一个规模巨大的过程，成人平均生成约 250 万个红细胞为了维持这种令人印象深刻的输出，红细胞的终末成熟与每秒的红细胞数量相结合。在 3-4 次细胞分裂期间，红系细胞必须将其细胞核压缩到大约 10 倍。其原始体积的 1/10，以期进行摘除，这涉及到组织的戏剧性压实红细胞基因组的破坏与骨髓增生异常综合征（MDS）有关。然而，我们对先天性贫血的最新证据知之甚少。小组和其他人暗示变异组蛋白 H2A.X 是正常红细胞的重要组成部分该组蛋白 S139 (γ-H2A.X) 的磷酸化是 DNA 修复途径的早期特征。有助于广泛分布的DNA修复因子“焦点”的稳定性值得注意的是，我们观察到γ-的爆发。 H2A.X 病灶处于红细胞成熟的特定阶段，伴随着增殖的显着增加和复制率，以及核凝聚的最后阶段，我们追踪组蛋白 H2A.X 磷酸化信号直接向下游途径发出信号，从而完成染色质重塑（通过组蛋白交换）和压缩（通过诱导细胞凋亡）相关途径）。这些研究将为涉及的仍然不透明的过程提供机制上的见解。红细胞终末成熟，增强我们对表观遗传基因调控和染色质的理解压实，并阐明可导致贫血的红细胞生成缺陷的基础。