Journal
EPIGENETICS
Volume 9, Issue 12, Pages 1613-1625Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/15592294.2014.988048
Keywords
epigenetic; Ewing sarcoma; HOX; polycomb; ARMS; alveolar rhabdomyosarcoma; BM-MSC; adult bone marrow-derived mesenchymal stem cells; ChIP; chromatin immunoprecipitation; ChIP-seq; chromatin immunoprecipitation; high throughput sequencing; ERMS; embryonal rhabdomyosarcoma; ES; Ewing sarcoma; GCR; global control region; hESC; human embryonic stem cells; HOX; homeobox; MSC; mesenchymal stem cells; NC-MSC; neural crest stem cell-derived mesenchymal stem cells; NCSC; neural crest stem cells; OS; osteosarcoma; PCA; principal components analysis; PRE; polycomb response element; qPCR; quantitative polymerase chain reaction; RT-PCR; reverse transcriptase polymerase chain reaction
Funding
- University of Michigan's Cancer Center Support Grant [P30 CA046592]
- NIH/NCI [T32 009676]
- European framework program 7 [259348]
- Austrian Science Fund [M1448-B13]
- [R01-CA134604]
- [SU2C-AACR-IRG1309]
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The polycomb proteins BMI-1 and EZH2 are highly overexpressed by Ewing sarcoma (ES), a tumor of stem cell origin that is driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. In the current study we analyzed expression of transcription programs that are controlled by polycomb proteins during embryonic development to determine if they are abnormal in ES. Our results show that polycomb target gene expression in ES deviates from normal tissues and stem cells and that, as expected, most targets are relatively repressed. However, we also discovered a paradoxical up regulation of numerous polycomb targets and these were highly enriched for homeobox (HOX) genes. Comparison of HOX profiles between malignant and non-malignant tissues revealed a distinctive HOX profile in ES, which was characterized by overexpression of posterior HOXD genes. In addition, ectopic expression of EWS-FLI1 during stem cell differentiation led to aberrant up regulation of posterior HOXD genes. Mechanistically, this up regulation was associated with altered epigenetic regulation. Specifically, ES and EWS-FLI1+ stem cells displayed a relative loss of polycomb-dependent H3K27me3 and gain of trithorax-dependent H3K4me3 at the promoters of posterior HOXD genes and also at the HOXD11.12 polycomb response element. In addition, a striking correlation was evident between HOXD13 and other genes whose regulation is coordinately regulated during embryonic development by distal enhancer elements. Together, these studies demonstrate that epigenetic regulation of polycomb target genes, in particular HOXD genes, is altered in ES and that these changes are mediated downstream of EWS-FLI1.
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