The role of long noncoding RNAs in regulating pancreas development and function

 描述（由申请人提供）：从历史上看，人们认为RNA在细胞中的主要功能是编码蛋白质，而蛋白质反过来仅负责基因调控。近几十年来，这些概念受到了挑战，因为发现真核基因组编码大量功能性非蛋白编码RNA（ncRNA），例如长非编码RNA（lncRNA），定义为长度超过200个核苷酸的转录本，缺乏蛋白编码潜力。此后，在许多细胞类型和不同的模式生物中鉴定了数千种lncRNA;然而，除了一些重要的例外，它们的功能大多是未知的。已被仔细分析的lncRNA调节过程，如印记，剂量补偿，多能性和凋亡。有趣的是，lncRNA可以通过直接与转录因子结合或通过募集染色质修饰复合物来顺式或反式调节基因的表达。此外，几种lncRNA已显示通过改变剪接或mRNA稳定性在转录后发挥作用。这些复杂的lncRNA调控机制的建立需要重新评估lncRNA作用背景下的生物学问题。虽然证据表明lncRNA在疾病相关胰腺中的作用，但缺乏胰腺lncRNA的功能表征。为了了解lncRNA如何促进胰腺的正常发育和功能，我们对胚胎小鼠胰腺和成年小鼠胰岛进行了全面的转录组分析。我们的初步研究结果揭示了几种新的胰腺lncRNA，它们与胰腺相关基因非常接近，并且在人类中在句法上和序列上都是保守的。此外，这些新的lncRNA以提示功能的时间方式表达。本研究将试图表征胰腺lncRNA并确定其功能机制。通过这些分析，我们可以发现一个新的基因调控层，并大大提高我们对促进胰腺发育和维持功能性成人胰腺的复杂调控机制的理解。

 DESCRIPTION (provided by applicant): Historically, it was thought that the primary function of RNA in a cell was to code for proteins and proteins, in turn, were solely responsible for gene regulation. These notions have been challenged in recent decades by the discovery that the eukaryotic genome codes for a vast number of functional non-protein-coding RNAs (ncRNAs), such as long noncoding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides that lack protein-coding potential. Thousands of lncRNAs have since been identified in numerous cell types and different model organisms; however, with a few important exceptions, their function is mostly unknown. The lncRNAs that have been carefully analyzed regulate processes as varied as imprinting, dosage compensation, pluripotency and apoptosis. Intriguingly, lncRNAs can regulate the expression of genes in cis or in trans by direct binding to transcription factors or by recruiting chromatin-modifying complexes. Additionally, several lncRNAs have been shown to function post-transcriptionally by altering splicing or mRNA stability. The establishment of these complex lncRNA regulatory mechanisms invokes a need to reassess biological questions in the context of a role for lncRNAs. While evidence suggests a role for lncRNAs in the disease- relevant pancreas, functional characterization of pancreatic lncRNAs is lacking. To understand how lncRNAs promote proper pancreas development and function, we have conducted comprehensive transcriptome analysis of embryonic mouse pancreas and adult mouse islets. Our preliminary results revealed several novel pancreatic lncRNA that lie in close proximity to pancreas-related genes and are both syntentically and sequentially conserved in humans. Additionally, these novel lncRNAs are expressed in a temporal manner suggestive of function. This study will seek to characterize pancreatic lncRNAs and determine their mechanism of function. With these analyses, we can uncover a novel layer of gene regulation and greatly enhance our understanding of the complex regulatory mechanisms that promote pancreas development and maintain a functional adult pancreas.