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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）：摘要随着发现大多数转录组是非编码RNA，具有基因调控功能的非编码RNA开始被视为哺乳动物基因调控的共同特征。鉴于基因组的很大一部分编码非编码 RNA，人们对这些 RNA 的调控机制和功能知之甚少。因此，对非编码 RNA 如何调控以及它们如何调控基因表达的新见解对于全面了解哺乳动物基因表达至关重要。我们利用 X 染色体失活作为模型系统来研究非编码 RNA 的调控和功能。 X 失活是雌性细胞中一条 X 染色体的发育调节转录沉默，用于平衡雄性细胞中的 X 连锁基因剂量。一对反义非编码 RNA Xist 和 Tsix RNA 在 X 失活的调节中发挥着核心作用。 X 失活是随机的 - 来自每个亲本的 X 染色体以相同的频率沉默。 Xist 和 Tsix RNA 在 X 染色体沉默开始之前表达，并且是随机发生 X 失活所必需的。在 Xist 或 Tsix 突变细胞中，X 失活是非随机的，突变体和野生型 X 染色体的命运是固定的。 Xist 和 Tsix 突变对 X 染色体命运具有相反的影响：Xist 突变染色体始终被选为活性 X，Tsix 突变 X 染色体始终被选为非活性 X。Xist 和 Tsix 还负向调节彼此的表达，形成反馈循环。在本提案中，我们剖析了 Xist/Tsix 反馈循环，并探讨如何使用它来确保每个 X 染色体具有相同的沉默频率。