Control of hematopoietic maturation by Lin28b/let-7

（请保持文字，不要PDF） 该项目植根于临床观察，即影响婴儿，儿童和成人的血液疾病不同。我们假设这是由于造血干细胞和祖细胞（HSPCs）的基本特性的发育和年龄相关的内在差异。我们的研究小组专注于了解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先前关于异时Lin 28 b/let-7轴在定义最终HSPC成熟状态中的作用的研究。Lin 28 b/let-7充当分子开关，由此Lin 28 b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、红细胞偏向输出和先天样淋巴细胞。Lin 28 b的发育下调释放let-7 microRNA，其靶向转录物以建立成熟的成人骨髓偏向性造血。我们已经发现，Polycomb阻遏复合物1（PRC 1）组分Cbx 2是造血系统中let-7 microRNA的靶点，PRC 1控制主造血转录因子（TF）如Erg的表达。基于这一发现，我们假设组蛋白H2 A赖氨酸119单泛素化（H2 AK 119 Ub）由PRC 1下游的Lin 28 b/let-7调节TF网络，控制HSPC自我更新和分化。该提案旨在了解1）Lin 28 b如何正常发育下调以及它如何在具有癌胚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作为主造血TF如何影响Lin 28 b/let-7/Cbx 2对造血成熟的控制。我们在正常造血成熟、血液病建模方面的经验，以及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理解年龄偏见性血液病。

(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.