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Elucidation of the Role of Setd8 and H4K20me1 in Erythropoiesis

阐明 Setd8 和 H4K20me1 在红细胞生成中的作用

基本信息

批准号：
10330585
负责人：
LAURIE A. STEINER
金额：
$ 33.88万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330585
关键词：
Acetylation Affect Anemia Cell Cycle Cell division Chromatin Chromatin Structure Complex Data Defect Disease Dysmyelopoietic Syndromes Enhancers Enzymes Epigenetic Process Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Failure Funding Gene Expression Gene Expression Profile Gene Silencing Goals Health Hematopoietic Higher Order Chromatin Structure Histone H4 Histones Human Impairment Inherited Laboratories Link Lysine Mass Spectrum Analysis Mediating Methylation Modeling Nuclear Nucleosomes Output Pathway interactions Physical condensation Play Population Post-Translational Protein Processing Preparation Process Production Proteins Reader Red Blood Cell Count Regulation Role Tail Testing Time Transcriptional Regulation cell type condensin design gene repression histone methylation histone methyltransferase insight novel progenitor recruit stem cells transcriptome

项目摘要

Chromatin condensation is a key feature in the terminal maturation of many hematopoietic cell types, but is particularly critical in erythroblasts, which undergo rapid nuclear and chromatin condensation in preparation for enucleation. The average human must generate ~2.5 million red blood cells per second to maintain steady state and avoid anemia. The process of generating an enucleate red blood cell from a committed erythroid progenitor is extremely complex, and requires significant in gene expression during a time of rapid cell division and chromatin condensation. Defects in chromatin condensation are particularly common in inherited anemias and myelodysplastic syndromes, however the specific epigenetic mechanisms that regulate erythroid chromatin condensation, and the relationship between chromatin condensation and gene expression are poorly understood. The goal of this project is to delineate specific epigenetic mechanisms that regulate, and coordinate, changes in gene expression and chromatin structure during terminal erythroid maturation. During the last funding period, we demonstrated that maturing erythroid cells accumulate mono-methylation of histone H4, lysine 20 (H4K20me1). We further demonstrated Setd8, the sole enzyme capable of generating this mark, is essential for erythropoiesis. Disruption of Setd8, and subsequent loss of H4K20me1, resulted in a profound defect in transcriptional repression and defects in chromatin condensation, both globally and at specific loci. The overall goal of this proposal is to delineate mechanisms by which Setd8 and H4K20me1 regulate erythropoiesis. Mass spectrometry studies demonstrated that accumulation of H4K20me1 in maturing erythroblasts was accompanied by loss of histone H4 K16Ac, which interferes with the association of neighboring nucleosomes and promotes histone decompaction, as well as loss of histone H4 lysine 20 dimethylation (H4K20me2), which decreases the ability of histone H4 lysine 20 to interact with epigenetic readers. We hypothesize that this epigenetic transition is an important determinate of gene expression and higher order chromatin structure in maturing erythroblasts. In specific Aim 1, we will determine the mechanisms that establish the H4 chromatin landscape in maturing erythroblasts. H4K20me1 regulates chromatin structure and gene expression through recruitment of epigenetic readers. The only H4K20me1 interacting protein expressed at significant levels in erythroblasts is the Condensin II complex. We demonstrate that the Condensin II subunit NCAPH2 is essential for erythropoiesis. Further, there is significant overlap in the transcriptomes of NCAPH2 / and SETD8 / erythroblasts, supporting a model where Condensin II interacts with H4K20me1 to regulate gene expression and chromatin structure during erythroid maturation. In specific aim 2, we will delineate the mechanisms by which the Condensin II complex regulates terminal erythroid maturation. Together, these studies will provide novel insights into the regulation of terminal erythroid maturation. As chromatin condensation is a common feature of the terminal maturation of many cell types, these studies may have broad implications beyond erythropoiesis.

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