Control of hematopoietic maturation by Lin28b/let-7

(请保存在Word中，不要保存为PDF) 这个项目植根于临床观察，即影响婴儿、儿童和成人的血液疾病是不同的。我们假设这是由于发育和年龄相关的造血干细胞和祖细胞(HSPC)的基本特性的内在差异。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。支持这一建议的初步数据扩展了我们之前关于异时性Lin28b/let-7轴在确定HSPC成熟状态中的作用的研究。Lin28b/let-7作为一个分子开关，在胎儿状态下表达Lin28b，以实现幼年造血的特征，如胎儿珠蛋白表达、偏向红系的输出和先天类淋巴细胞。发育下调的Lin28b释放let-7microRNAs，靶向转录，建立成熟的成人髓系偏向造血。我们已经发现，在造血系统中，多梳抑制物复合体1(Polycomb repressor Complex 1，PRC1)的成分Cbx2是let-7 microRNAs的靶标，并且PRC1控制着主要的造血转录因子(TF)的表达，如ERG。根据这一发现，我们假设组蛋白H_2A赖氨酸119由Lin28b/let-7下游的PRC1单糖基化(H_2AK119Ub)调节控制HSPC自我更新和分化的TF网络。本研究旨在了解1)Lin28b在正常发育过程中如何下调，以及在骨髓增生异常综合征等具有癌胎儿基因表达的血液疾病中如何异常表达；2)Erg作为一种主要的造血转铁蛋白，如何影响Lin28b/let-7/Cbx2‘S调控造血成熟。我们在正常造血成熟、血液疾病建模方面的经验，以及我们为完成这项拟议的研究而建立的合作，使我们能够回答这些关键问题，我们相信这些问题对于更好地理解年龄偏见的血液疾病具有直接的应用价值。

(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.