Imprinted snoRNA loci and circadian entrainment

充足的睡眠对于最佳的代谢、认知和心理健康至关重要。昼夜 影响睡眠行为的节律是由基因决定的，但环境却由 外部线索，如光暴露。昼夜节律夹带预计将建立由 人们对表观遗传机制知之甚少，这些机制使哺乳动物能够适应它们的新陈代谢， 环境哺乳动物的睡眠和昼夜代谢模式是不同的， 与SNORD 116小核仁RNA（snoRNA）重复序列的获得相一致， Prader-Willi综合征（PWS）基因座。PWS基因座是印记的，这意味着基因 仅在父本而非母本染色体15 q11-q13区域表达， 使役的PWS是由SNORD 116编码的两种非编码RNA的丢失引起的。 首先，SNORD 116 snoRNA定位于成熟神经元中的核仁，并影响rRNA， 核仁成熟第二，SNORD 116 snoRNA侧翼的宿主基因外显子是 剪接并作为长的非编码RNA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转录、DNA甲基化和 新陈代谢. SNORD 116的内含子序列表现出高GC偏斜，促进了基因的表达。 DNA：RNA杂交结构的形成称为R环。R环促进染色质 解凝聚，减缓转录进程，并保护DNA甲基化。 有趣的是，母体过表达类似结构的大印迹snoRNA簇， 14号染色体上的突变导致PWS相关的Temple综合征，已发表的证据支持 这两个印记基因座的交叉调节。在我们最近对表观遗传变化的分析中 与昼夜节律和Snord 116基因座相关，> 23，000个节律性甲基化 在野生型小鼠皮质中观察到CpG，其中97%在小鼠皮质中丢失或时移。 Snord 116 +/-同窝仔。这些Snord 116影响的甲基化增强子和启动子 具有高度富集的昼夜节律夹带和体重功能的调节基因， 包括坦普尔综合征基因座内的基因在这一建议中，我们试图理解 Snord 116在昼夜节律夹带中的作用及其表观遗传机制 调控基因表达的节律性昼夜周期，重点是 印迹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，并可能使未来的表观遗传疗法， 印记障碍此外，确定非编码RNA如何调节昼夜节律， 睡眠/觉醒周期中的表观遗传节律和代谢来改变表型是一种 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，心理健康和影响几乎所有人的体重问题。

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.