Abstract
Genetic instability plays a key role in the formation of naturally occurring cancer. The formation of long DNA palindromes is a rate-limiting step in gene amplification, a common form of tumor-associated genetic instability. Genome-wide analysis of palindrome formation (GAPF) has detected both extensive palindrome formation and gene amplification, beginning early in tumorigenesis, in an experimental Myc-induced model tumor system in the chicken bursa of Fabricius. We determined that GAPF-detected palindromes are abundant and distributed nonrandomly throughout the genome of bursal lymphoma cells, frequently at preexisting short inverted repeats. By combining GAPF with chromatin immunoprecipitation (ChIP), we found a significant association between occupancy of gene-proximal Myc binding sites and the formation of palindromes. Numbers of palindromic loci correlate with increases in both levels of Myc over-expression and ChIP-detected occupancy of Myc binding sites in bursal cells. However, clonal analysis of chick DF-1 fibroblasts suggests that palindrome formation is a stochastic process occurring in individual cells at a small number of loci relative to much larger numbers of susceptible loci in the cell population and that the induction of palindromes is not involved in Myc-induced acute fibroblast transformation. GAPF-detected palindromes at the highly oncogenic bic/miR-155 locus in all of our preneoplastic and neoplastic bursal samples, but not in DNA from normal and other transformed cell types. This finding indicates very strong selection during bursal lymphomagenesis. Therefore, in addition to providing a platform for gene copy number change, palindromes may alter microRNA genes in a fashion that can contribute to cancer development.
Highlights
Oncogenic deregulation of the c-myc protooncogene was first reported in lymphomas of the chicken bursa of Fabricius resulting from Avian Leukosis Virus (ALV) insertional mutagenesis [1,2]
By combining genome-wide analysis of palindrome formation (GAPF) with chromatin immune precipitation (ChIP) we discovered an association between palindrome formation and the occupancy of nearby Myc binding sites in chromatin, and, report a strong selection for palindrome formation at an oncogenic micro RNA gene, bic/miR-155, known to cooperate with c-myc in bursal lymphomagenesis [19,20,21]
Using a Myc oncogene-induced lymphoma model system, this paper describes clustering of tumor-specific palindromes throughout the genome as well as an association of sites of palindrome formation with both preexisting short inverted DNA repeat sequences and occupied Myc DNAbinding sites
Summary
Oncogenic deregulation of the c-myc protooncogene was first reported in lymphomas of the chicken bursa of Fabricius resulting from Avian Leukosis Virus (ALV) insertional mutagenesis [1,2]. Extensive investigation of deregulated expression of c-Myc more broadly implicates this oncoprotein in a wide variety of animal and human neoplasms [5,6] as a significant contributor to many of the key processes underlying cancer [7] These tumor-related phenotypes include genomic instability [8,9,10], which is thought to be essential for the development of most naturally occurring cancers. A functional genomics tool for the genome-wide analysis of palindrome formation (GAPF) recently has been developed and used to detect the widespread presence of palindromes in human cancer [17,18] We adapted this technique to interrogate this Myc-induced tumor system [11], and detected extensive palindrome formation in early TF and end-stage lymphomas. The population of loci showing amplification by array CGH was enriched for palindromes detected by GAPF providing strong evidence for genetic instability early in Mycinduced tumorigenesis and further support for the role of palindromes in gene amplification
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