Control of hematopoietic maturation by Lin28b/let-7

Lin28b/let-7 对造血成熟的控制

• 批准号: 10559039
• 负责人: Robert Grant Rowe
• 金额: $ 35.4万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559039
• 关键词: Adolescent; Adult; Affect; Age; Aging; Biological Assay; Blood; Cell Maturation; Cells; Child; Clinical; Collaborations; Complement; Data; Development; Developmental Biology; Disease; Down-Regulation; Dysmyelopoietic Syndromes; Ectopic Expression; Enhancers; Equilibrium; Erythroid; Family; Fetal Hemoglobin; Gene Combinations; Gene Expression; Gene Expression Profiling; Genetic Transcription; Globin; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Histone H2A; Histones; Immune system; Infant; Investigation; Knowledge; Laboratories; Lymphocyte; Lysine; Maps; MicroRNAs; Modeling; Molecular; Mus; Myelogenous; Organism; Outcome; Output; Pathway interactions; Pattern; Plant Roots; Polycomb; Positioning Attribute; Process; Property; RNA-Binding Proteins; Regulation; Repression; Repressor Proteins; Research; Role; System; Testing; Transcript; age related; blood formation; experience; fetal; hematopoietic stem cell aging; hematopoietic stem cell self-renewal; improved; innovation; knock-down; overexpression; paralogous gene; pediatric patients; programs; self-renewal; stem cell function; transcription factor

(PLEASE KEEP IN WORD, DO NOT PDF) This project is rooted in the clinical observation that the blood diseases that affect infants, children, and adults differ. We hypothesize that that is due to developmental and age-related intrinsic differences in the fundamental properties of hematopoietic stem and progenitor cells (HSPCs). Our research group is focused on understanding how temporal differences in HSPCs impact manifestation of blood diseases. The preliminary data supporting this proposal expand our prior studies on the role of the heterochronic Lin28b/let-7 axis in defining the maturation states of definitive HSPCs. Lin28b/let-7 acts as a molecular switch whereby Lin28b is expressed in the fetal state to implement hallmarks of juvenile hematopoiesis such as fetal globin expression, erythroid-biased output, and innate-like lymphocytes. Developmental downregulation of Lin28b releases let-7 microRNAs that target transcripts to establish mature adult myeloid-biased hematopoiesis. We have found that the Polycomb repressor complex 1 (PRC1) component Cbx2 is a target of let-7 microRNAs in the hematopoietic system and that PRC1 controls the expression of master hematopoietic transcription factors (TFs) such as Erg. On the basis of this finding, we hypothesize that histone H2A lysine 119 monoubiquitylation (H2AK119Ub) by PRC1 downstream of Lin28b/let-7 regulates the TF networks that control HSPC self-renewal and differentiation. This proposal aims to understand 1) how Lin28b is normally developmentally downregulated and how it may be aberrantly expressed in blood diseases with oncofetal gene expression such as myelodysplastic syndrome; and 2) how Erg, as a master hematopoietic TF, effects Lin28b/let-7/Cbx2’s control of hematopoietic maturation. Our experience in normal hematopoietic maturation, modeling of blood diseases, and the collaborations that we have established to complete this proposed research position us to answer these key questions, which we believe have immediate applications to better understanding age-biased blood diseases.

（请以 WORD 形式保存，请勿以 PDF 形式保存） 该项目源于临床观察，即影响婴儿、儿童和成人的血液疾病有所不同，我们认为这是由于造血干细胞和祖细胞 (HSPC) 的基本特性与发育和年龄相关的内在差异所致。我们的研究小组致力于了解 HSPC 的时间差异如何影响血液疾病的表现，支持这一提议的初步数据扩展了我们之前关于异时性 Lin28b/let-7 轴在定义确定性成熟状态中的作用的研究。 Lin28b/let-7 充当分子开关，Lin28b 在胎儿状态下表达，以实现幼年造血的标志，例如胎儿珠蛋白表达、红细胞偏向输出和 Lin28b 释放 let- 的先天性下调。 7 个 microRNA 靶向转录物以建立成熟的成体骨髓偏向造血作用，我们发现 Polycomb 阻遏物复合体 1。 (PRC1) 成分 Cbx2 是造血系统中 let-7 microRNA 的靶标，并且 PRC1 控制主要造血转录因子 (TF) 的表达，例如 Erg。根据这一发现，我们进行了组蛋白 H2A 赖氨酸 119 单泛素化。 Lin28b/let-7 下游的 PRC1 (H2AK119Ub) 调节控制 HSPC 的 TF 网络该提案旨在了解 1) Lin28b 在正常情况下如何在发育过程中下调，以及它如何在具有癌胎儿基因表达的血液疾病（如骨髓增生异常综合征）中异常表达；以及 2) Erg 作为主要造血因子如何，影响 Lin28b/let-7/Cbx2 对造血成熟的控制 我们在正常造血成熟、血液疾病建模和方面的经验。我们为完成这项拟议研究而建立的合作使我们能够回答这些关键问题，我们相信这些问题可以立即应用于更好地了解年龄偏向性血液疾病。