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）维持生命长的血液产生并获得体细胞突变，导致 前具有克隆膨胀和骨髓增生综合征（MDS）。真核基因组在层次上是 以不同的空间水平组织。但是，在很大程度上尚不清楚该高阶三维（3D）如何 基因组组织协调基因表达的坐标调节发育命运的基因表达 决定。核层粘蛋白是结构蛋白，可建立基因组结构并发挥重要作用 在干细胞和疾病中。 lamin b1是造血细胞中最丰富的核层蛋白，其表达 由于MDS中的5Q缺失，在衰老中大大减少。但是，我们缺乏基本 了解层粘连B1如何调节基因组组织，该3D组织如何影响HSC命运 决策以及LMNB1的5Q缺失是否有助于MDS的发病机理和进展。 在这里，我们建议系统地回答这些杰出的问题，以获得对 lamin B1如何促进正常和MDS造血。我们的团队由一个干细胞生物学家组成 血液学疾病建模（Doulatov）的专业知识，这是一位具有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（贵族）专业知识的计算生物学家，以及具有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 人类造血的层lamin b1损失。这些实验表明，层粘连B1损失改变了染色质 组织和核形态和促进HSC和髓样细胞的命运，而以淋巴细胞的为代价。 我们建议在这些初步研究基础上进行如下：AIM 1，确定层粘连蛋白B1和LBR在 人体HSC功能和体内克隆动力学； AIM 2，定义lamin B1如何调节染色质结构 控制HSC命运的基因表达； AIM 3，确定LMNB1的5Q缺失是否构成受损 DEL5Q MDS中的造血。这些研究的意义在于它们将阐明层粘连蛋白依赖性 3D基因组调节HSC命运。健康相关性是拟议的工作可以将层lamin b1识别为 DEL5Q MDS中的肿瘤抑制剂。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脆弱性。