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.

抽象的 造血干细胞 (HSC) 维持终生血液生成并获得体细胞突变，从而导致 癌前克隆扩张和骨髓增生异常综合征（MDS）。真核生物基因组是分层的 组织在不同的空间层次上。然而，目前尚不清楚这种高阶三维 (3D) 基因组组织协调协调调控发育命运背后的基因表达 决定。核纤层蛋白是建立基因组结构并发挥重要作用的结构蛋白 在干细胞和疾病方面。 Lamin B1 是造血细胞中最丰富的核纤层蛋白，其表达 随着年龄的增长以及 MDS 中反复出现的 5q 缺失，该值普遍下降。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，该 3D 组织如何影响 HSC 命运 决定，以及 LMNB1 的 5q 缺失是否有助于 MDS 的发病机制和进展。 在这里，我们建议系统地回答这些悬而未决的问题，以获得对 核纤层蛋白 B1 如何促进正常和 MDS 造血。我们的团队由一名干细胞生物学家组成 血液疾病建模方面的专业知识 (Doulatov)，一位具有 3D 基因组专业知识的分子生物学家 (Duan)，具有 3D 基因组专业知识的计算生物学家 (Noble)，以及具有 3D 基因组专业知识的生物化学家 染色质调节（Escobar）。在初步研究中，我们检查了分子和功能后果 核纤层蛋白 B1 损失对人类造血的影响。这些实验表明核纤层蛋白 B1 缺失会改变染色质 组织和核形态，并以牺牲淋巴细胞生成为代价促进 HSC 和骨髓细胞的命运。 我们建议以这些初步研究为基础，如下：目标 1，确定核纤层蛋白 B1 和 LBR 在 人 HSC 功能和体内克隆动态；目标 2，定义核纤层蛋白 B1 如何调节染色质结构 以及控制 HSC 命运的基因表达；目标 3，确定 LMNB1 的 5q 缺失是否导致受损 del5q MDS 中的造血作用。这些研究的意义在于它们将阐明核纤层蛋白依赖性如何 3D 基因组调控 HSC 命运。与健康相关的是，拟议的工作可能会将核纤层蛋白 B1 确定为 del5q MDS 中的肿瘤抑制因子。由于 5q 缺失通常与高风险 MDS 相关，因此这些研究将有助于 确定主要的遗传驱动因素并探索这种疾病的治疗漏洞。