Long non-coding RNAs in hematopoiesis and blood malignancy

 描述(由申请人提供)：最近对人类基因组进行功能注释的努力表明，高达75%的DNA在转录方面是活跃的。由于我们基因组中只有一小部分编码蛋白质，许多人假设这种普遍存在的转录过程中的一部分会导致产生长的非编码RNA。通过生成与染色质特征相集成的高深度RNA-Seq数据集，我们的实验室和其他实验室已经揭示了数千个以前未注释的lncRNA的存在，它们在不同的细胞环境中响应各种刺激而动态表达。尽管取得了这些令人信服的进展，但绝大多数假定的lncRNA尚未被证明在功能上是重要的，尽管一小部分显然已被证明发挥了关键的调节作用。最重要的是，人们对lncRNAs在人类癌症中的生物学作用知之甚少。在这里，我们结合深度转录组测序、高分辨率转录因子定位图和染色质相互作用数据，首次全面鉴定和表征了T细胞急性淋巴细胞白血病(T-ALL)中lncRNA的表达和功能。T-ALL是一种由致癌基因NOTCH1转录活性驱动的侵袭性血液系统恶性肿瘤。此外，我们提供了第一张以癌基因(NOTCH1)为靶点的LncRNAs图谱，并确定了一个单独的LncRNA(称为LUNAR1)，它似乎对肿瘤的生长至关重要，因为它控制着细胞因子(IGF1)信号。这些研究表明：a)lncRNAs可被用作人类癌症的生物标志物和治疗靶点(见AIM1)，b)需要更有效的方法来大规模推断和验证lncRNA功能以充分了解它们的生物学意义(见AIM2)，以及c)LUNAR1是最早能够控制急性白血病生长的lncRNAs之一，也是一个潜在的治疗靶点(见AIM3)。在本申请中，我们详细讨论了所有这些重要的问题，并试图将lncRNA失控与白血病的发生和发展直接联系起来。

 DESCRIPTION (provided by applicant): Recent efforts to functionally annotate the human genome have revealed that up to 75% of our DNA is transcriptionally active. Since a very small portion of our genome encodes proteins many have hypothesized that a portion of this pervasive transcription results in production of long non-coding RNA. By generating high depth RNA-Seq datasets integrated with chromatin features, our lab and others have revealed the presence of many thousands of previously un-annotated lncRNAs, which are dynamically expressed in response to various stimuli in diverse cellular contexts. Despite these compelling advances, the vast majority of putative lncRNAs have not been proven to be functionally important, although a small portion have clearly been shown to play key regulatory roles. Most importantly, very little is known on the biological role of lncRNAs in human cancer. We provide here, using a combination of deep transcriptome sequencing, high-resolution transcription factor occupancy mapping and chromatin interaction data, the first comprehensive identification and characterization of lncRNA expression and function in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic malignancy driven by oncogenic NOTCH1 transcriptional activity. Moreover, we provide the first map of oncogene (NOTCH1)-targeted lncRNAs in this tumor and identify an individual lncRNA (called LUNAR1) that appears to be essential for tumor growth as it controls cytokine (IGF1) signaling. These studies suggest that: a) lncRNAs could be used as both biomarkers and therapy targets in human cancer (see AIM1), b) more efficient methods for large-scale inference and validation of lncRNA function are needed to fully understand their biological significance (see AIM2) and, c) LUNAR1 is one of the first lncRNAs that can control growth of acute leukemia and a potential therapeutic target (see AIM3). In this application we address in detail all these important issues and attempt to directly connect lncRNA deregulation to leukemia initiation and progression.