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（由申请人提供）：从历史上看，人们认为细胞中 RNA 的主要功能是编码蛋白质，而蛋白质反过来又完全负责基因调控。近几十年来，这一发现对这些观念提出了挑战。真核基因组编码大量功能性非蛋白质编码 RNA (ncRNA)，例如长非编码 RNA (lncRNA)，其定义为长度超过 200 个核苷酸的转录本，缺乏此后，在多种细胞类型和不同的模型生物体中发现了数千种 lncRNA；然而，除了一些重要的例外，经过仔细分析的 lncRNA 的功能大多是未知的。有趣的是，lncRNA 可以通过直接结合转录因子或通过招募染色质修饰复合物来调节顺式或反式基因的表达。 lncRNA 已被证明通过改变剪接或 mRNA 稳定性来发挥作用，这些复杂的 lncRNA 调节机制的建立需要重新评估 lncRNA 的作用背景下的生物学问题，而证据表明 lncRNA 在疾病中的作用。 - 缺乏相关的胰腺、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，我们对胚胎小鼠进行了全面的转录组分析。我们的初步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，并且在人类中都是同构和顺序保守的。此外，这些新的lncRNA以时间方式表达，暗示了其功能。研究将寻求表征胰腺 lncRNA 并确定其功能机制，通过这些分析，我们可以揭示新的基因调控层，并极大地增强我们对促进胰腺发育和维持胰腺功能的复杂调控机制的理解。有功能的成人胰腺。