Imprinted snoRNA loci and circadian entrainment

印记 snoRNA 位点和昼夜节律夹带

• 批准号: 10535437
• 负责人: Janine M LaSalle
• 金额: $ 48.9万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535437
• 关键词: Affect; Basic Science; Behavior; Behavioral; Binding Sites; Body Weight; Body mass index; Brain; Cell Nucleolus; Cell Nucleus; Cerebral cortex; Chromatin; Chromosome 14; Chromosome Structures; Chromosomes; Circadian Rhythms; Cognitive; Compulsive Hoarding; Coupled; Cues; DNA; DNA Methylation; DNA Repair; Darkness; Disease; Dissection; Drowsiness; Energy Metabolism; Enhancers; Environment; Epigenetic Process; Evolution; Exhibits; Exons; Feeding behaviors; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genomic Imprinting; Genotype; Hour; Human; Hybrids; Hyperphagia; Individual; Inherited; Intellectual functioning disability; Knowledge; Light; Link; Liver; Mammals; Maps; Measures; Mediating; Mental Health; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methylation; Molecular; Molecular Analysis; Molecular Genetics; Monitor; Mus; Nervous System; Neurodevelopmental Disorder; Neurons; Obesity; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Organism; Periodicity; Phenotype; Post-Translational Protein Processing; Prader-Willi Syndrome; Proteins; Publishing; RNA; RNA Splicing; Regulation; Respiration; Ribosomal RNA; Risk; Role; Sampling; Seasons; Signal Transduction; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Small Nucleolar RNA; Structure; Syndrome; System; Testing; Time; Transgenic Mice; Untranslated RNA; Weight; Wild Type Mouse; autism spectrum disorder; circadian; circadian pacemaker; demethylation; epigenetic regulation; epigenetic therapy; epigenome; experimental group; experimental study; feeding; genome wide methylation; genome-wide; genome-wide analysis; genomic locus; histone modification; imprint; improvement on sleep; insight; light entrainment; mental function; methylation pattern; mouse model; neuropsychiatric disorder; overexpression; promoter; sleep behavior; sleep pattern; theories; trait; transcription factor

Sufficient sleep is essential for optimal metabolic, cognitive, and mental health. Circadian rhythms affecting sleep behavior are genetically determined, but environmentally entrained by external cues such as light exposure. Circadian entrainment is predicted to be established by poorly understood epigenetic mechanisms that allow mammals to adapt their metabolism to the environment. Distinct patterns of sleep and diurnal metabolism have evolved within mammals, coinciding with the acquisition of SNORD116 small nucleolar RNA (snoRNA) repeats in the Prader-Willi syndrome (PWS) locus. The PWS locus is imprinted, meaning that genes expressed only on the paternal but not the maternal chromosome 15q11-q13 region are causative. PWS is caused by the loss of two types of noncoding RNAs encoded by SNORD116. First, SNORD116 snoRNAs localize to the nucleolus in maturing neurons and impact rRNA and nucleolar maturation. Second, the host gene exons flanking the SNORD116 snoRNAs are spliced and retained in the nucleus as a long noncoding RNA, forming a large RNA cloud structure that regulates transcription of circadian transcription factors, DNA methylation, and metabolism. The intronic sequences of SNORD116 exhibit high GC skew, promoting the formation of DNA:RNA hybrid structures called R-loops. R-loops promote chromatin decondensation, slow transcriptional progression, and protect from DNA methylation. Interestingly, maternal overexpression of a similarly structured large imprinted snoRNA cluster on chromosome 14 causes PWS-related Temple syndrome, and published evidence supports the cross-regulation of these two imprinted loci. In our recent analyses of epigenetic changes associated with circadian rhythmicity and the Snord116 locus, >23,000 rhythmic methylated CpGs were observed in wild-type mouse cortex, of which 97% were lost or time-shifted in Snord116+/- littermates. These Snord116-impacted methylation enhancers and promoters regulated genes with functions highly enriched for circadian entrainment and body weight, including genes within the Temple syndrome locus. In this proposal, we seek to understand the role of Snord116 in circadian entrainment and the epigenetic mechanisms underlying Snord116 regulation of rhythmic circadian cycles of gene expression genome-wide, with a focus on imprinted snoRNA loci. The results of these experiments are expected to expand functional knowledge of imprinted noncoding RNAs and potentially enable future epigenetic therapies for imprinting disorders. In addition, determining how noncoding RNAs regulate circadian epigenetic rhythms and metabolism during sleep/wake cycles to modify phenotypes is an emerging basic science field. These studies may therefore have profound future impacts on improving sleep, mental health, and weight problems that affect almost all humans.

足够的睡眠对于最佳的代谢，认知和心理健康至关重要。昼夜节律 影响睡眠行为的节奏是遗传确定的，但在环境上被环保 外部线索，例如光曝光。预计昼夜节律将由 较少了解的表观遗传机制使哺乳动物能够使其新陈代谢适应 环境。哺乳动物中的不同睡眠和昼夜代谢的不同模式已经发展 与获取Snord116小核仁RNA（SNORNA）重复相吻合 Prader-Willi综合征（PWS）基因座。 PWS基因座是印刷的，这意味着基因 仅以父亲的身份表示，但不在父亲15q11-Q13区域的染色体染色体 因果关系。 PWS是由SNORD116编码的两种类型的非编码RNA丢失引起的。 首先，Snord116 snornas位于成熟神经元中的核仁，并撞击rRNA和 核仁成熟。其次，宿主基因外显子两侧是Snord116 snornas 剪接并保留在细胞核中，作为长的非编码RNA，形成大RNA云 调节昼夜节律转录因子，DNA甲基化和 代谢。 SNORD116的内含子序列表现出高GC偏斜，促进了 DNA的形成：称为R环的RNA杂交结构。 R环促进染色质 调节性，转录进展缓慢并免受DNA甲基化的保护。 有趣的是，类似结构的大型印迹snorna簇的母体过表达 关于14号染色体会导致与PWS相关的寺庙综合征，并发表证据支持 这两个印迹基因座的交叉调节。在我们最近对表观遗传变化的分析中 与昼夜节律和SNORD116基因座有关，> 23,000节奏甲基化 在野生型小鼠皮层中观察到CPG，其中97％丢失或迁移。 snord116 +/-乱货物。这些SNORD116受影响的甲基化增强剂和启动子 受调节的基因具有高度丰富昼夜节律和体重的功能， 包括神庙综合征基因座中的基因。在此提案中，我们试图了解 SNORD116在昼夜节律中的作用和Snord116的表观遗传机制 调节基因表达基因组的节奏昼夜节律，重点 印迹的snorna loci。这些实验的结果有望扩大功能 了解印迹的非编码RNA，并有可能使未来的表观遗传疗法成为 烙印疾病。另外，确定非编码RNA如何调节昼夜节律 睡眠/唤醒周期中以修饰表型的表观遗传节奏和代谢是一种 新兴的基础科学领域。因此，这些研究可能对未来对 改善几乎所有人类的睡眠，心理健康和体重问题。

项目成果

Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex.

• DOI: 10.1038/s41467-018-03676-0
• 发表时间: 2018-04-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Coulson RL;Yasui DH;Dunaway KW;Laufer BI;Vogel Ciernia A;Zhu Y;Mordaunt CE;Totah TS;LaSalle JM
• 通讯作者: LaSalle JM