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In Aim 2, satellite RNAs will be examined in cancer, based on unpublished findings showing gross overexpression of satellite II RNA in many cancer samples.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.
- Relevance to Public Health The proposed research sets out to advance the knowledge of the structural changes that occur to individual cells upon the initiation and progression of cancer. The combined approach of using human embryonic stem cells in conjunction with cancer cell lines and tumor samples will allow for an in-depth analysis of the relationship between satellite DNA and structural changes in cellular reorganization. An understanding of how these events may be initiated will allow for a greater understanding of how and why cancer progresses.
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