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性注释的努力表明，高达75%的DNA具有转录活性。由于我们的基因组中只有一小部分编码蛋白质，因此许多人假设这种普遍转录的一部分导致了长的非编码RNA的产生。通过生成与染色质特征集成的高深度RNA-Seq数据集，我们的实验室和其他实验室已经揭示了数千种以前未注释的lncRNA的存在，这些lncRNA在不同的细胞环境中响应于各种刺激而动态表达。尽管有这些引人注目的进展，但绝大多数推定的lncRNA尚未被证明具有重要的功能，尽管一小部分已明确显示出发挥关键的调控作用。最重要的是，人们对lncRNA在人类癌症中的生物学作用知之甚少。我们在这里提供，使用深度转录组测序，高分辨率转录因子占有率映射和染色质相互作用数据的组合，第一次全面鉴定和表征lncRNA表达和功能的T细胞急性淋巴细胞白血病（T-ALL），一个积极的血液恶性肿瘤驱动的致癌NOTCH 1转录活性。此外，我们提供了该肿瘤中癌基因（NOTCH 1）靶向lncRNA的第一个图谱，并确定了一个单独的lncRNA（称为LUNAR 1），该lncRNA似乎对肿瘤生长至关重要，因为它控制细胞因子（IGF 1）信号传导。这些研究表明：a）lncRNA可用作人类癌症中的生物标志物和治疗靶标（参见AIM 1），B）需要用于大规模推断和验证lncRNA功能的更有效方法以充分理解其生物学意义（参见AIM 2），以及c）LUNAR 1是可控制急性白血病生长的第一种lncRNA和潜在的治疗靶标之一（参见AIM 3）。在本申请中，我们详细讨论了所有这些重要问题，并试图将lncRNA失调与白血病的发生和进展直接联系起来。

 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.