The role of lamin B1 in normal and myelodysplastic hematopoiesis

核纤层蛋白 B1 在正常和骨髓增生异常造血中的作用

• 批准号: 10707829
• 负责人: Sergei Doulatov
• 金额: $ 57.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707829
• 关键词: 3-Dimensional; Abnormal Neutrophil; Aging; Architecture; Bar Codes; Binding; Biology; Blood; Blood Cells; Cell Lineage; Cell Nucleus; Cells; Chromatin; Chromatin Loop; Chromosomes; Clonal Expansion; Collaborations; Computer Analysis; Development; Disease; Disease model; Distal; Dysmyelopoietic Syndromes; Elements; Enhancers; Equilibrium; Euchromatin; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Impairment; Inherited; Lamin B1; Lamins; Lymphoid; Lymphopoiesis; Molecular; Morphology; Mutation; Myelogenous; Myeloid Cells; Nuclear; Nuclear Lamin; Pathogenesis; Pelger-Huet Anomaly; Phenocopy; Play; Process; Production; Proteins; Recurrence; Regulation; Role; Somatic Mutation; Specific qualifier value; Structural Protein; Testing; Therapeutic; Three-dimensional analysis; Tumor Suppressor Proteins; Work; body system; cell fate specification; chromosome 5q loss; experimental study; hematopoietic stem cell fate; hematopoietic stem cell self-renewal; high risk; in vivo; induced pluripotent stem cell; lamin B receptor; pharmacologic; premalignant; programs; promoter; self-renewal; stem; stem cell fate specification; stem cell function; stem cell model; stem cells; transcription factor

ABSTRACT Hematopoietic stem cells (HSCs) maintain life-long blood production and acquire somatic mutations leading to premalignant clonal expansion and myelodysplastic syndromes (MDS). Eukaryotic genomes are hierarchically organized at distinct spatial levels. However, it is largely unclear how this higher order three-dimensional (3D) genome organization orchestrates coordinate regulation of gene expression underlying developmental fate decisions. Nuclear lamins are structural proteins that establish genome architecture and play a prominent role in stem cells and disease. Lamin B1 is the most abundant nuclear lamin in hematopoietic cells, and its expression is broadly decreased in aging and due to recurrent 5q deletions in MDS. However, we lack a fundamental understanding of how lamin B1 regulates genome organization, how this 3D organization impacts HSC fate decisions, and whether 5q deletion of LMNB1 contributes to MDS pathogenesis and progression. Here, we propose to systematically answer these outstanding questions to gain a fundamental understanding of how lamin B1 contributes to normal and MDS hematopoiesis. Our team consists of a stem cell biologist with expertise in hematologic disease modeling (Doulatov), a molecular biologist with expertise in 3D genomes (Duan), computational biologist with expertise in 3D genomes (Noble), and a biochemist with expertise in chromatin regulation (Escobar). In preliminary studies, we examined the molecular and functional consequences of lamin B1 loss on human hematopoiesis. These experiments revealed that lamin B1 loss alters chromatin organization and nuclear morphology and promotes HSC and myeloid cell fates at the expense of lymphopoiesis. We propose to build on these preliminary studies as follows: Aim 1, Determine the role of lamin B1 and LBR in human HSC function and clonal dynamics in vivo; Aim 2, Define how lamin B1 regulates chromatin architecture and gene expression to control HSC fate; Aim 3, Determine whether 5q deletion of LMNB1 underlies impaired hematopoiesis in del5q MDS. The significance of these studies is that they will elucidate how lamin-dependent 3D genome regulates HSC fate. The health relevance is that the proposed work may identify lamin B1 as a tumor suppressor in del5q MDS. Since 5q deletion is often associated with high-risk MDS, these studies will help identify a major genetic driver and explore therapeutic vulnerabilities for this disorder.

摘要 造血干细胞（HSC）维持终生的血液生产并获得体细胞突变，导致造血干细胞的死亡。 癌前克隆扩增和骨髓增生异常综合征（MDS）。真核生物的基因组是分等级的 在不同的空间层次。然而，很大程度上还不清楚这种高阶三维（3D） 基因组组织协调基因表达的调节，这是发育命运的基础 决策核纤层蛋白是一种结构蛋白，它建立了基因组的结构，并发挥着突出的作用 干细胞和疾病核纤层蛋白B1是造血细胞中最丰富的核纤层蛋白，其表达 随着年龄的增长和MDS中复发性5 q缺失而广泛降低。然而，我们缺乏一个基本的 了解核纤层蛋白B1如何调节基因组组织，这种3D组织如何影响HSC命运 决定，以及LMNB 1的5 q缺失是否有助于MDS发病机制和进展。 在这里，我们建议系统地回答这些悬而未决的问题，以获得一个基本的理解， 核纤层蛋白B1如何促进正常和MDS造血。我们的团队由一位干细胞生物学家组成， 血液病建模专家（Doulatov），具有3D基因组专业知识的分子生物学家 （段），计算生物学家与3D基因组（诺布尔）的专业知识，和生物化学家与专业知识， 染色质调节（Escobar）。在初步研究中，我们检查了分子和功能的后果， 核纤层蛋白B1缺失对人类造血的影响。这些实验表明，核纤层蛋白B1的缺失改变了染色质 组织和核形态，并促进HSC和骨髓细胞的命运，以淋巴细胞生成为代价。 我们建议在这些初步研究的基础上进行如下研究：目的1，确定核纤层蛋白B1和LBR在 体内人HSC功能和克隆动力学;目标2，定义核纤层蛋白B1如何调节染色质结构 目的3，确定LMNB 1的5 q缺失是否是受损的基础 del 5 q MDS中的造血。这些研究的重要性在于，它们将阐明层粘连蛋白依赖性 3D基因组调控HSC命运。健康相关性是，拟议的工作可能会确定核纤层蛋白B1作为一种 del 5 q MDS中的肿瘤抑制因子。由于5 q缺失通常与高危MDS相关，这些研究将有助于 确定一个主要的遗传驱动因素，并探索这种疾病的治疗漏洞。