The repeat genome in interphase chromosome structure and regulation

描述（申请人提供）：值得注意的是，几乎一半的人类基因组由散布的重复元件组成，但对这些元件的分析并不是近年来基因组科学中令人印象深刻的进展之一。事实上，这些占据所有人类染色体的高拷贝重复序列通常从基因组研究中筛选出来，因为它们带来了技术挑战并阻碍了标准的分子方法。对这种大量重复序列缺乏关注也是由于它们的低序列保守性和其他特性，这些特性导致人们普遍认为它们是不相关的进化“垃圾”。根据我们实验室和其他实验室最近的证据，我们认为这一教条正在改变，“重复基因组”不仅包含有意义的生物学，而且可能是染色体结构和基因组表观遗传调控的基础。通过探测，而不是掩盖，RNA从重复原位，我们发现了强有力的证据，高拷贝重复元件产生丰富的核RNA，这是嵌入在核染色体结构。我们的研究结果表明，这些RNA是不良提取的标准方法的分子测定。我们拥有一支强大的跨学科团队，他们将以创新和多方面的方法解决重复序列研究的这一挑战和其他挑战。这项研究有可能建立一个突破性的概念：以前认为沉默的散布重复序列使RNA成为染色体结构和调控的组成部分。与已建立的ncRNA（如XIST）诱导异染色质或基因沉默的范例相反，我们假设重复RNA可以促进开放常染色质，并可能竞争相同结构蛋白的结合。除了在核RNA分析和染色体生物学方面的非凡实力外，我们的团队还在RNA生物化学和重复序列的生物信息学方面具有非凡的实力。

DESCRIPTION (provided by applicant): Remarkably, almost half the human genome consists of interspersed repetitive elements, but in analysis of these has not been among the many impressive advances in genome science in recent years. In fact, these high copy repeats populating all human chromosomes are routinely screened out of genomic studies, as they pose technical challenges and thwart standard molecular approaches. The lack of attention to this large mass of repeats is also due to their low sequence conservation and other properties which have led to the widely held belief that they are irrelevant evolutionary "junk". Based on recent evidence from our lab and others, we propose that this dogma is changing, and that the "repeat genome" not only contains-meaningful biology, but is likely fundamental to chromosome structure and epigenetic regulation of the genome. By probing, rather than masking, RNA from repeats in situ, we discovered strong evidence that high copy repeat elements produce abundant nuclear RNAs, which are embedded in nuclear chromosome structure. Our findings suggest that these RNAs are poorly extracted by standard methods for - molecular assays. We have a strong interdisciplinary team who will address this and other challenges to the - study of repeat sequences with innovative and multi faceted approaches. This research has potential to establish a ground breaking concept: that interspersed repeats previously thought silent make RNAs that are integral to the structure and regulation of chromosomes. In contrast to the established paradigm of ncRNAs (e.g. XIST) inducing heterochromatin or gene silencing, we hypothesize that repeat RNAs can promote open euchromatin, and may compete for binding of the same structural protein. In addition to unusual strength in nuclear RNA analysis and chromosome biology, our team includes exceptional strength in RNA biochemistry and bioinformatics of repeat sequences.