Heterochromatin instability and misregulation of noncoding RNA in cancer

描述（由申请人提供）：近50%的人类基因组由非编码DNA元件组成，包括染色体着丝粒和臂间区大块的几种类型的串联卫星重复序列。虽然卫星长期以来被认为是沉默的，但最近的证据表明，卫星重复序列可以表达，但其表达的程度和调控或其潜在功能仍有待阐明。由于它们在对细胞分裂至关重要的区域内的关键位置，预计这些序列的严格调控对于表观遗传和遗传稳定性都是必不可少的。这项提议将建立在强有力的初步结果的基础上，这些结果表明卫星RNA调控可能对干细胞和癌细胞生物学都很重要。目的1将进一步建立在胚胎干细胞分化过程中着丝粒卫星表达上调的初步数据基础上。令人惊讶的是，我们最近的研究结果还表明，多能干细胞的着丝粒异染色质在结构上不同于谱系定向体细胞。此外，卫星RNA上调出现时间与成熟的“体细胞型”异染色质，这表明一个潜在的功能联系。在目标2中，将在癌症中检查卫星RNA，基于未发表的发现，这些发现显示许多癌症样品中卫星II RNA的过度表达。众所周知，表观遗传变化在癌症中可能很重要，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和卫星甲基化的丧失，但尚未专门研究卫星RNA的失调。将对癌细胞系和癌组织类型的调查分析卫星RNA的过表达，优先将其确定为癌症的共同标志，并最终确定特定癌症亚型和阶段中表达基因座的子集（“卫星RNA特征”）。卫星表达的变化将构成癌细胞生物学的一个基本上未知但潜在重要的方面，直接影响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特征”可以作为癌症早期检测和预后的生物标志物。

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 In Aim 2, satellite RNAs will be examined in cancer, based on unpublished findings showing gross overexpression of satellite II RNA in many cancer samples.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.