The Role of Long Noncoding RNA in Hematopoiesis

摘要 Hox基因对于维持细胞自我更新和分化之间的平衡至关重要。 造血干细胞（HSC）。虽然HoxB4基因在骨髓或骨髓中的异位表达， 胚胎干细胞（ESCs）导致的显着扩增和长期移植的潜力， HSC，HoxB4缺陷小鼠在胎肝中仅表现出祖细胞和干细胞的轻度减少 和骨髓。相比之下，HoxB3和HoxB4基因缺陷的小鼠表现出严重的 造血缺陷伴HSC群显著减少，表明其他前HoxB 基因可以与HoxB4合作来指定造血细胞的命运。重要的是要了解 前HoxB基因协同激活以赋予HSC的潜在机制 命运Hox基因的表达在表观遗传学上受多梳（PcG）和三胸（TrxG）的调控 集团监管机构。我们发现，在HoxB4基因座上募集SETD1A基因决定了它的表达。 转录激活和促进HSC命运。此外，我们还鉴定并克隆了一个HoxB基因， 基因座相关的长基因间非编码RNA（lincRNA），HoxBlinc，在 与H3K4me3模式和前HoxB基因一致的早期造血分化 activation.此外，HoxBlinc与Setd1a HMT复合物结合，并控制细胞的生长。 Flk1+成血管细胞的特化和分化。因此，数据表明，HoxBlinc RNA 可能在早期造血中发挥重要作用，至少部分通过募集Setd1a HMT复合物 从而调节Hox基因座染色质结构和组织。但委员会仍 目前尚不清楚HoxBlinc如何重新编程染色质状态来调节前HoxB基因， 造血特异性转录程序以及HoxBlinc是否在靶向组蛋白中发挥作用 修饰这些基因的酶以启动造血分化。根据我们初步的 数据，我们假设Setd1a HMT复合物选择性募集到HoxB基因座， 前HoxB表达的协调由HoxBlinc介导，以指定造血细胞 命运在这个提议中，我们将研究HoxBlinc在染色质状态重编程中的作用， 调节前部HoxB基因转录。我们将探讨潜在的表观遗传机制， 其中HoxBlinc调节早期造血谱系定型和分化。通过完成 提出的研究，我们期望更好地了解lincRNA和 表观遗传调节因子控制造血的早期事件。

Abstract Hox genes are critical for maintaining the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs). Although ectopic expression of the HoxB4 gene in bone marrow or embryonic stem cells (ESCs) leads to a dramatic expansion and long-term engraftment potential of HSCs, HoxB4 deficient mice exhibit only a mild reduction in progenitors and stem cells in fetal liver and bone marrow. In contrast, mice deficient in both HoxB3 and HoxB4 genes display severe hematopoietic defects with a marked decrease in HSC population indicating that other anterior HoxB genes may cooperate with HoxB4 to specify hematopoietic cell fate. It is important to understand underlying mechanisms by which the anterior HoxB genes are coordinately activated to confer HSC fate. The expression of Hox genes is regulated epigenetically by polycomb (PcG) and trithorax (TrxG) group regulators. We showed that recruitment of SETD1A to the HoxB4 locus governs its transcription activation and promotes HSC fate. Furthermore, we have identified and cloned a HoxB locus associated long intergenic noncoding RNA (lincRNA), HoxBlinc, which is expressed during early hematopoietic differentiation consistent with H3K4me3 patterns and anterior HoxB gene activation. Furthermore, HoxBlinc associates with the Setd1a HMT complex and controls the specification and differentiation of Flk1+ hemangioblasts. Thus, the data suggest that HoxBlinc RNA may play an important role in early hematopoiesis, at least in part by recruiting Setd1a HMT complexes onto the Hox genes thereby modulating Hox locus chromatin structure and organization. However, it remains unknown how HoxBlinc reprograms chromatin state to regulate anterior HoxB genes and hematopoietic specific transcription program and whether HoxBlinc plays a role in targeting histone modifying enzymes to these genes to initiate hematopoietic differentiation. Based on our preliminary data, we hypothesize that selective recruitment of the Setd1a HMT complex to the HoxB locus and coordination of anterior HoxB expression are mediated by HoxBlinc to specify the hematopoietic cell fate. In this proposal, we will examine the role of HoxBlinc in reprograming chromatin state and modulating anterior HoxB gene transcription. We will investigate underlying epigenetic mechanism by which HoxBlinc regulates early hematopoietic lineage commitment and differentiation. By finishing the proposed research, we expect a better understanding of molecular mechanism by which lincRNA and epigenetic regulators control early events of hematopoiesis.