Locus-specific regulation of pericentric satellite sequences
Abstract: The intent of this proposed research is to contribute to the basic understanding of the structure and function of specific DNA sequences found near chromosomal centromeres – constricted regions to which spindle fibers attach, enabling duplicated chromosomes to segregate to opposite poles of a dividing cell. Despite extensive sequencing of the human genome, the specific DNA sequences within the centromere and the adjacent regions (the pericentromere) are vastly unknown, due to their highly repetitive nature. It is known that the DNA sequences residing within the centromere and pericentromere are subject to strict regulation, such that they are not normally transcribed into RNA. Intriguingly, we have recently uncovered a tandemly repeated pericentric satellite sequence, HSATII, which is aberrantly transcribed into RNA in cancer cells. While HSATII DNA is found on eleven different human chromosomes, only a few of these locations transcribe HSATII RNA in cancer cells, suggesting that the regulation and sequence composition may vary from one chromosome to another. Thus, a full analysis of the HSATII sequences residing on individual human chromosomes is long overdue and merited, and promises to further drive studies to uncover the consequence of pericentric satellite transcription in cancer progression. The goals of the current proposal are to define chromosome-specific subsets of HSATII DNA sequences in the human genome and to harness that information to test the role of HSATII RNA in promoting uncontrolled cell growth. Due to their critical location near centromeres during cell division, we hypothesize that the presence of aberrant satellite RNA may lead to cell division defects and chromosomal instability. The project to be conducted will also engage and train promising undergraduate researchers in innovative genomics and cytological techniques, which will propel future careers in genomics and cancer research.