Imprinted snoRNA loci and circadian entrainment

印记 snoRNA 位点和昼夜节律夹带

• 批准号: 10319981
• 负责人: Janine M LaSalle
• 金额: $ 51.25万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319981
• 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; Measures; Mediating; Mental Health; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methylation; Molecular; Molecular Analysis; Molecular Genetics; Monitor; Mus; Nervous system structure; 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; 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; genome-wide analysis; genomic locus; histone modification; imprint; improved; 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.

充足的睡眠对于最佳的新陈代谢、认知和心理健康至关重要。昼夜节律 影响睡眠行为的节律是由基因决定的，但受环境影响 外部线索，例如光照。昼夜节律夹带预计将通过以下方式建立 人们对表观遗传机制知之甚少，而这些机制使哺乳动物能够适应其新陈代谢 环境。哺乳动物进化出了独特的睡眠和昼夜代谢模式， 与 SNORD116 小核仁 RNA (snoRNA) 重复序列的获得同时发生 普瑞德威利综合征 (PWS) 位点。 PWS 基因座有印迹，这意味着基因 仅在父本染色体 15q11-q13 区域表达，而不在母本染色体 15q11-q13 区域表达 因果。 PWS 是由 SNORD116 编码的两种非编码 RNA 丢失引起的。 首先，SNORD116 snoRNA 定位于成熟神经元的核仁并影响 rRNA 和 核仁成熟。其次，SNORD116 snoRNA 侧翼的宿主基因外显子是 剪接并作为长非编码RNA保留在细胞核中，形成大的RNA云 调节昼夜节律转录因子转录、DNA 甲基化和 代谢。 SNORD116 的内含子序列表现出高 GC 偏差，促进 DNA:RNA 杂合结构（称为 R 环）的形成。 R 环促进染色质 解缩合、减缓转录进程并防止 DNA 甲基化。 有趣的是，母体过度表达类似结构的大印记 snoRNA 簇 14 号染色体上的 14 号染色体导致与 PWS 相关的 Temple 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 与昼夜节律和 Snord116 基因座相关，>23,000 个节律甲基化 在野生型小鼠皮层中观察到 CpG，其中 97% 在 Snord116+/- 同窝小鼠。这些受 Snord116 影响的甲基化增强子和启动子 调节基因的功能高度丰富，可调节昼夜节律和体重， 包括Temple综合征基因座内的基因。在本提案中，我们试图了解 Snord116 在昼夜节律夹带中的作用以及 Snord116 的表观遗传机制 调节全基因组基因表达的节律昼夜节律周期，重点是 印迹 snoRNA 位点。这些实验的结果预计将扩展功能 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 睡眠/觉醒周期期间的表观遗传节律和代谢来改变表型是一种 新兴基础科学领域。因此，这些研究可能会对未来产生深远的影响 改善几乎影响所有人的睡眠、心理健康和体重问题。