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Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers.

ABSTRACT: Satellite repeats in heterochromatin are transcribed into noncoding RNAs that have been linked to gene silencing and maintenance of chromosomal integrity. Using digital gene expression analysis, we showed that these transcripts are greatly overexpressed in mouse and human epithelial cancers. In 8 of 10 mouse pancreatic ductal adenocarcinomas (PDACs), pericentromeric satellites accounted for a mean 12% (range 1 to 50%) of all cellular transcripts, a mean 40-fold increase over that in normal tissue. In 15 of 15 human PDACs, alpha satellite transcripts were most abundant and HSATII transcripts were highly specific for cancer. Similar patterns were observed in cancers of the lung, kidney, ovary, colon, and prostate. Derepression of satellite transcripts correlated with overexpression of the long interspersed nuclear element 1 (LINE-1) retrotransposon and with aberrant expression of neuroendocrine-associated genes proximal to LINE-1 insertions. The overexpression of satellite transcripts in cancer may reflect global alterations in heterochromatin silencing and could potentially be useful as a biomarker for cancer detection.

SUBMITTER: Ting DT

PROVIDER: S-EPMC3701432 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Publications

Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers.

Ting David T DT Lipson Doron D Paul Suchismita S Brannigan Brian W BW Akhavanfard Sara S Coffman Erik J EJ Contino Gianmarco G Deshpande Vikram V Iafrate A John AJ Letovsky Stan S Rivera Miguel N MN Bardeesy Nabeel N Maheswaran Shyamala S Haber Daniel A DA

Science (New York, N.Y.) 20110113 6017

Satellite repeats in heterochromatin are transcribed into noncoding RNAs that have been linked to gene silencing and maintenance of chromosomal integrity. Using digital gene expression analysis, we showed that these transcripts are greatly overexpressed in mouse and human epithelial cancers. In 8 of 10 mouse pancreatic ductal adenocarcinomas (PDACs), pericentromeric satellites accounted for a mean 12% (range 1 to 50%) of all cellular transcripts, a mean 40-fold increase over that in normal tissu ...[more]

PMID: 21233348

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Project description:During meiosis, chromosomes must find, pair and synapse with their homologous partner in the crowded milieu of the nucleus, without being entangled by non-homologous chromosomes1. Generally, homology detection is thought to rely on recombination between the homologous chromosomes. However, pairing and synapsis can occur in the absence of recombination2–10, suggesting alternate mechanisms which discriminate between homologous and non-homologous associations. In many eukaryotes, tandem repeats known as satellite DNA are known to facilitate inter-chromosomal associations11. Notably, their non-uniform distribution across chromosomes gives rise to homologue-specific satellite DNA ‘barcodes’12–14, which have been speculated to enable meiotic pairing15–18. However, the inability to manipulate these repeats in most model organisms means that satellite DNA function in meiotic pairing remains actively debated. Here, we use satellite DNA deletion, duplication, and translocation strains that are unique to Drosophila to demonstrate that repeat mismatches perturb meiotic pairing, particularly at centromeres and pericentromeres. Strains containing satellite DNA mismatches exhibit pairing defects that are likely driven by the incorrect association of similar repeats on non-homologous chromosomes. Notably, defective pairing also occurs in the progeny of D. melanogaster natural populations that have diverged in their satellite DNA content. In the absence of homozygous satellite DNA arrays, we further show that pairing is antagonized by the HORMAD protein, Mad2, while a Pachytene checkpoint 2 (Pch2)-dependent meiotic delay can restore pairing. Finally, compromised meiotic pairing is strongly correlated with mid-oogenesis cell death, a quality control mechanism that likely culls defective oocytes to prevent chromosome mis-segregation and aneuploidy. Therefore, our findings resolve the debate on satellite DNA functionality by providing evidence for a role in meiotic pairing. We propose that this repeat-based pairing mechanism exerts an underappreciated selective pressure, constraining the divergence of these rapidly evolving tandem repeats within interbreeding natural populations.

Dataset Information

Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers.

Publications

Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers.

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