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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：
10432108
负责人：
MICHAEL D BULGER
金额：
$ 30.21万
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/10432108
关键词：
Acinus organ component Address Adult 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 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 Knock-out Knockout Mice Light Mediating Molecular Chaperones Mus Mutation Non-Malignant Nuclear Output Pathway interactions Pattern Phosphorylation Physical condensation Preparation Process Research Role Serine Signal Transduction Site Tail Testing United States National Institutes of Health Variant base chromatin remodeling design gene repression 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，成年人平均产生约250万个红细胞