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

长链非编码RNA在调节胰腺发育和功能中的作用

• 批准号: 9150295
• 负责人: Ruth A Singer
• 金额: $ 4.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150295
• 关键词: Adult; Alpha Cell; Animal Model; Antisense RNA; Apoptosis; Beta Cell; Binding; Binding Sites; Biological; Biological Process; Cell Differentiation process; Cell Line; Cell physiology; Cells; Chromatin; Code; Complex; Data; Developmental Biology; Developmental Gene; Diabetes Mellitus; Disease; Dosage Compensation (Genetics); Embryo; Epigenetic Process; Etiology; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Human; In Vitro; Islet Cell; Islets of Langerhans; Knockout Mice; Knowledge; Maps; Methods; Mus; Mutant Strains Mice; Neuroblastoma; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Pancreas; Pancreatic Diseases; Pattern; Phenotype; Process; Proteins; RNA; RNA Binding; RNA Splicing; Recruitment Activity; Regulation; Regulator Genes; Regulatory Element; Regulatory Pathway; Replacement Therapy; Role; Suggestion; Susceptibility Gene; Technology; Testing; Tissues; Transcript; Transcriptional Regulation; Translating; Untranslated RNA; Variant; beta cell replacement; cell type; experimental study; falls; genome wide association study; genome-wide; imprint; in vitro Assay; in vivo; induced pluripotent stem cell; islet; knock-down; mRNA Stability; mammalian genome; novel; pancreas development; pluripotency; public health relevance; transcription factor; transcriptome; transcriptome sequencing

 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.

 描述(申请人提供)：过去，人们认为RNA在细胞中的主要功能是编码蛋白质，而蛋白质则只负责基因调控。近几十年来，由于发现真核生物基因组编码了大量功能性非蛋白质编码RNA(NcRNAs)，如长非编码RNA(LncRNAs)，这些概念受到了挑战，lncRNAs是指长度超过200个核苷酸的转录本，缺乏蛋白质编码能力。自那以后，在众多的细胞类型和不同的模式生物中已经发现了数千个lncRNA；然而，除了少数重要的例外，它们的功能大多是未知的。经过仔细分析的lncRNAs调控的过程包括印迹、剂量补偿、多能性和细胞凋亡。有趣的是，lncRNAs可以通过直接与转录因子结合或通过招募染色质修饰复合体来调节顺式或反式基因的表达。此外，一些lncRNAs已被证明通过改变剪接或mRNA的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在lncRNA的作用范围内重新评估生物学问题。虽然有证据表明lncRNAs在与疾病相关的胰腺中发挥作用，但缺乏对胰腺lncRNAs功能的描述。为了了解lncRNAs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。我们的初步结果揭示了几个新的胰腺lncRNA，它们位于与胰腺相关的基因附近，并且在人类中同时和序列上都是保守的。此外，这些新的lncRNA以一种提示功能的时间方式表达。本研究将致力于研究胰腺LncRNAs的特性，并确定其作用机制。通过这些分析，我们可以发现一个新的基因调控层，并极大地提高我们对促进胰腺发育和维持成人胰腺功能的复杂调控机制的理解。