Regulation of Xist RNA processing in embryonic stem cells

胚胎干细胞中 Xist RNA 加工的调控

基本信息

批准号：
8508949
负责人：
BARBARA PANNING
金额：
$ 27.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): ABSTRACT Non-coding RNAs with gene regulatory functions are starting to be seen as a common feature of mammalian gene regulation with the discovery that most of the transcriptome is non-coding RNA. Given that a significant proportion of the genome encodes non-coding RNAs, relatively little is known about the regulatory mechanisms and functions of these RNAs. Thus, new insights into how non-coding RNAs are regulated and how they regulate gene expression are essential for a complete understanding of mammalian gene expression. We employ X chromosome inactivation as a model system to study the regulation and function of non-coding RNAs. X-inactivation is the developmentally regulated transcriptional silencing of one X chromosome in female cells, used to equalize X-linked gene dosage with male cells. An antisense pair of non-coding RNAs, Xist and Tsix RNA, are central in the regulation of X-inactivation. X-inactivation is random - the X chromosome from each parent is silenced with equal frequency. Xist and Tsix RNA are expressed before the onset of X chromosome silencing and are necessary for X-inactivation to occur randomly. In Xist or Tsix mutant cells, X-inactivation is non-random and the fates of the mutant and the wild-type X chromosomes are fixed. Xist and Tsix mutations have opposite effects on X chromosome fate: an Xist mutant chromosome is always chosen as the active X and a Tsix mutant X chromosome is always chosen as the inactive X. Xist and Tsix also negatively regulate each other's expression, forming a feedback loop. In this proposal we dissect the Xist/Tsix feedback loop and explore how it is used to ensure that each X chromosome has an equal frequency of being silenced.

描述（由申请人提供）：带有基因调节功能的抽象非编码RNA开始被视为哺乳动物基因调节的常见特征，发现大多数转录组是非编码RNA的发现。鉴于很大一部分基因组编码非编码RNA，因此对这些RNA的调节机制和功能相对较少。因此，关于如何调节非编码RNA以及它们如何调节基因表达的新见解对于完全理解哺乳动物基因表达至关重要。我们利用X染色体灭活作为模型系统来研究非编码RNA的调节和功能。 X灭活是雌性细胞中一个X染色体的发育调节的转录沉默，用于将X连锁基因剂量与雄性细胞均衡。一对反义的非编码RNA，XIST和TSIX RNA在X灭活的调节中是中心的。 X灭活是随机的 - 来自每个父的X染色体以相等的频率沉默。 XIST和TSIX RNA在X染色体沉默的发作之前表示，对于X灭活是随机发生的必要条件。在XIST或TSIX突变细胞中，X灭活是非随机的，突变体的命运和野生型X染色体是固定的。 XIST和TSIX突变对X染色体命运具有相反的作用：Xist突变染色体始终被选为活性X，并且始终选择A tSIX突变体X染色体作为无效的X染色体。XIST和TSIX还负面调节彼此的表达方式，形成反馈循环。在此提案中，我们剖析了XIST/TSIX反馈回路，并探索如何使用它来确保每个X染色体都具有相等的沉默频率。