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.

充足的睡眠对最佳的新陈代谢、认知和心理健康至关重要。昼夜

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