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.

充足的睡眠对最佳新陈代谢、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由基因决定的，但受环境因素的影响 外部信号，如光线曝光。据预测，昼夜节律夹带是由 鲜为人知的表观遗传机制使哺乳动物能够适应 环境。哺乳动物体内进化出了不同的睡眠和日间新陈代谢模式， 与获得SNORD116小核仁RNA(SnoRNA)在 Prader-Willi综合征(PWS)基因座。PWS基因座是印记的，这意味着基因 只在父亲染色体上表达，而不在母体染色体15q11-q13区域表达 有因果关系的。PWS是由SNORD116编码的两种非编码RNA的丢失引起的。 首先，SNORD116 snoRNAs定位于成熟神经元的核仁，并影响rRNA和 核仁成熟。其次，SNORD116 snoRNAs两侧的宿主基因外显子是 以长的非编码RNA的形式拼接并保留在细胞核中，形成一个大的RNA云 调节昼夜节律转录因子、DNA甲基化和 新陈代谢。SNORD116的内含子序列表现出高度的GC偏斜，促进了 DNA的形成：被称为R-环的RNA杂交结构。R环促进染色质 解缩，减缓转录进程，并保护DNA甲基化。 有趣的是，类似结构的大印记snoRNA簇的母体过表达 14号染色体上的基因导致PWS相关的坦普尔综合征，已发表的证据支持 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 与昼夜节律性和SNORD116基因座相关，&gt；23,000节律性甲基化 在野生型小鼠大脑皮质中观察到cpgs，其中97%的cpg丢失或时移。 SNORD116+/-窝产仔。这些受SNORD116影响的甲基化增强子和启动子 具有高度丰富的昼夜携带和体重功能的受调控基因， 包括坦普尔综合症基因座内的基因。在这项建议中，我们试图了解 SNORD116在昼夜携带中的作用及其表观遗传机制 全基因组基因表达节律昼夜节律周期的调节，重点是 印迹的snoRNA基因座。这些实验的结果有望扩展功能 印迹非编码RNA的知识，并有可能使未来的表观遗传疗法成为可能 印记障碍。此外，确定非编码RNA如何调节昼夜节律 在睡眠/清醒周期中改变表型的表观遗传节律和新陈代谢是一种 新兴的基础科学领域。因此，这些研究可能对未来产生深远的影响 改善睡眠、心理健康和体重问题，这些问题几乎影响到所有人类。

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