Noncoding RNAs at the heart of the Prader-Willi locus

Prader-Willi综合征(PWS)是一种具有已知遗传基因的神经发育障碍 病因学，但有复杂的表观遗传学基础。PWS是一种印记障碍，这意味着 只在父亲染色体上表达而不在母亲染色体15q11上表达的基因丢失- Q13区域致病。此外，与影响蛋白质的基因突变不同， 编码基因，导致PWS的最小基因缺失只影响非编码 RNA的转录本。在PWS中最小缺失区域的核心是两种类型的 非编码RNA。首先，SNORD116小核仁RNA(SnoRNAs)定位于 成熟神经元中的核仁并影响rRNA和核仁成熟。第二， SNORD116 snoRNAs周围的宿主基因外显子(116 HG)被拼接并 核内保留为长的非编码RNA(LncRNA)，形成大的云状RNA 调节每日表达的转录和代谢的结构。内含子 GC含量高的序列形成DNA：RNA混合结构，称为R-环 促进染色质解缩和减缓反义基因的转录进程 安杰曼综合征(AS)基因UBE3A的转录本。在这项建议中，我们寻求 回答三个关于慢性粒细胞白血病分子发病机制的主要问题 PWS。1)非编码需要哪些主要的遗传和细胞成分 RNA的定位和功能导致PWS表型？2)有什么影响 对PWS基因座的交叉调节机制的影响？3) 光/暗周期和温度的改变可用于优化雷帕霉素治疗 在PWS小鼠模型中？这些实验的结果有望得到改善。 了解位于PWS基因中心的lncRNAs的功能作用。

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology, but a complex epigenetic basis. PWS is an imprinted disorder, meaning that loss of genes expressed only on the paternal but not the maternal chromosome 15q11- q13 region cause disease. Furthermore, unlike genetic mutations that affect protein- coding genes, the smallest genetic deletions causing PWS only affect noncoding transcripts of RNA. At the heart of the minimally deleted region in PWS are two types of noncoding RNAs. First, the SNORD116 small nucleolar RNAs (snoRNAs) localize to the nucleolus in maturing neurons and impact rRNA and nucleolar maturation. Second, the host gene exons (116HG) surrounding the SNORD116 snoRNAs are spliced and nuclear retained as a long noncoding RNA (lncRNA), forming a large RNA cloud-like structure that regulates diurnally expressed transcription and metabolism. The intronic sequences with high GC skew form DNA:RNA hybrid structures called R-loops that promote chromatin decondensation and slow transcriptional progression of the antisense transcript to the Angelman syndrome (AS) gene UBE3A. In this proposal, we seek to answer three major unanswered questions regarding the molecular pathogenesis of PWS. 1) What are the major genetic and cellular components required for noncoding RNA localization and function leading to the PWS phenotypes? 2) What is the influence of diurnal time on the cross-regulatory mechanisms of the PWS locus? 3) Could alterations to light/dark cycles and temperature be used to optimize a rapamycin therapy in the PWS mouse model? The results of these experiments are expected to improve understanding of the functional role of the lncRNAs at the heart of the PWS locus.