Heterochromatin instability and misregulation of noncoding RNA in cancer

描述(申请人提供)：近50%的人类基因组由非编码DNA元件组成，包括几种类型的串联卫星重复序列，在染色体的中心和着丝点周围区域以大块形式存在。虽然卫星一直被认为是沉默的，但最近的证据表明，卫星重复序列可以表达，但其表达的范围和调节或其潜在功能仍有待阐明(S)。由于它们位于对细胞分裂至关重要的区域内，预计对这些序列的严格调控对表观遗传和遗传稳定性都是必不可少的。这项建议将建立在强有力的初步结果的基础上，表明卫星RNA调控可能对干细胞和癌细胞生物学都很重要。目标1将进一步建立在初步数据的基础上，即着丝粒卫星的表达在胚胎干细胞分化过程中上调。令人惊讶的是，我们最近的发现还表明，多能干细胞的着丝粒异染色质在结构上与血统相关的体细胞的结构不同。此外，卫星RNA的上调似乎在时间上与“体细胞型”异染色质的成熟有关，这表明了一种潜在的功能联系。在目标2中，将在癌症中检查卫星RNA，这是基于未发表的发现，显示在许多癌症样本中卫星II RNA严重过度表达。众所周知，表观遗传变化在癌症中可能是重要的，但研究主要集中在肿瘤抑制基因的不适当沉默(甲基化)上。虽然病理学家早就注意到癌症中异染色质组织的丧失和卫星甲基化，但对卫星RNA的错误调控还没有具体的研究。对癌症细胞系和癌症组织类型的调查将分析卫星RNA的过度表达，重点是将其确立为癌症的共同标志，并最终确定特定癌症亚型和阶段的表达座位子集(“卫星RNA签名”)。卫星表达的变化将包括癌细胞生物学中一个基本上未知但潜在重要的方面，直接涉及表观遗传和遗传不稳定性。从长远来看，在癌症样本中观察到的强大的“卫星RNA签名”可能会作为癌症早期检测和预后的生物标记物。

DESCRIPTION (provided by applicant): Nearly 50% of the human genome consists of non-coding DNA elements, including several types of tandem satellite repeats in large blocks at the centric and pericentric regions of chromosomes. While satellites were long thought to be silent, recent evidence indicates that satellite repeats can be expressed, but the extent and regulation of their expression or their potential function(s) remain to be elucidated. Due to their critical location within regions vital for cell division, it is expected that tight regulation of these sequences is essential for both epigenetic and genetic stability. This proposal will build on strong preliminary results suggesting satellite RNA regulation may be important to both stem cell and cancer cell biology. Aim 1 will further build upon preliminary data that expression of centromeric satellites is upregulated during differentiation of embryonic stem cells. Surprisingly, our recent findings also indicate that centromeric heterochromatin of pluripotent stem cells is structurally distinct from that of lineage committed somatic cells. Furthermore, satellite RNA upregulation appears temporally linked to maturation of "somatic type" heterochromatin, suggesting a potential functional link. In Aim 2, satellite RNAs will be examined in cancer, based on unpublished findings showing gross overexpression of satellite II RNA in many cancer samples. It is well known that epigenetic changes can be important in cancer, but studies have focused primarily on inappropriate silencing (methylation) of tumor suppressor genes. While pathologists have long noted the loss of heterochromatic organization and satellite methylation in cancer, misregulation of satellite RNAs has not been specifically studied. A survey of cancer cell lines and cancer tissue types will be analyzed for overexpression of satellite RNA with a priority to establish this as a common hallmark of cancer and to ultimately determine the subset of expressing loci ("satellite RNA signature") in specific cancer subtypes and stages. Changes in satellite expression would comprise an essentially unknown but potentially important aspect of cancer cell biology, with direct implication for both epigenetic and genetic instability. Over the longer-term, the robust "satellite RNA signature" observed within cancer samples may serve as a biomarker for early detection and prognosis of cancer.