Regulation of X-Inactivation by Non-Coding RNA Loci

哺乳动物通过早期雌性X染色体的转录沉默实现剂量补偿 发展X染色体失活（XCI）由一个称为“X失活中心”的主基因座控制， 一个顺式作用中心，这是必要的和足够的指导X染色体计数，选择，并启动 沉默我们的长期目标是了解每一步的分子基础。目前已知， RNA是X-失活中心的非编码产物，它“描绘”失活的X，并被要求启动全局性的X-失活。 沉默的X。上一个资助期的工作导致在X染色体上发现了两个新的非编码RNA基因座， 失活中心Tsix是Xist的反义基因，它抑制Xist的表达，并指定未来的活性X。Xite，a 与低水平基因间转录物相关的基因座，正调控Tsix表达。因此，所有已知的调节 X失活中心的元件产生非编码RNA。拟议的研究将剖析的机制， 由Tsix和Xite执行。具体而言，拟议的研究将（1）确定Xite和irsix如何抑制 Xist RNA，（2）定义X-失活印迹和选择的分子基础，以及（3）测试Xite是否是Xce（“X- 控制元件”），XCI等位基因比率的长期难以捉摸的修饰剂，其与不利的偏斜有关 X连锁疾病女性携带者中的XCI。作为哺乳动物中为数不多的反义基因座之一，Tsix作为一个范例， 进行反义调控。作为哺乳动物中仅有的两个已知的功能性基因间转录元件之一，Xite 推进这一新兴的基因间现象的有限的知识。从研究项目中获得的信息 也将对人类遗传学、癌症和动物克隆以及人类的基础生物学产生重大影响。 染色体、染色质结构和转录调控。

Mammals achieve dosage compensation by transcriptional silencing of one X-chromosome in early female development. X-chromosome inactivation (XCI) is controlled by a master locus known as the "X-inactivation center," a cis-acting center which is both necessary and sufficient to direct X-chromosome counting, choice, and initiation of silencing. Our long term goal is to understand the molecular underpinnings of each step. It is currently known that Xist RNA, a non-coding product of the X-inactivation center, "paints" the inactive X and is required to initiate global silencing of that X. Work from the last funding period led to the discovery of two novel non-coding RNA loci at the X- inactivation center. Tsix, a gene antisense to Xist, inhibits Xist expression and designates the future active X. Xite, a locus associated with low-level intergenic transcripts, positively regulates Tsix expression. Thus, all known regulatory elements at the X-inactivation center make non-coding RNA. The proposed research will dissect the mechanism of action by Tsix and Xite. Specifically, the proposed research will (1) determine how Xite and irsix inhibit the spread of Xist RNA, (2) define the molecular basis of X-inactivation imprinting and choice, and (3) test ifXite is the Xce ("X- controlling element"), the long-elusive modifier of XCI allele ratios which has been implicated in unfavorable skewing of XCI in female carriers of X-linked disease. As one of very few antisense loci in mammals, Tsix serves as a paradigm for antisense regulation. As one of only two known functional intergenic transcription elements in mammals, Xite will advance a limited knowledge of this emerging intergenic phenomenon. Information gained from the research program will also have significant impact on human genetics, cancer, and animal cloning, as well as on the basic biology of chromosomes, chromatin structure, and transcriptional regulation.