ribute to their heterogeneity may be key for SYT-SSX function. Our present observations suggest that the nature of these putative features may, at least in part, be epigenetically determined. Transcriptome analysis of hMSCSYT-SSX1 showed that a major SGI-7079 effect of SYT-SSX in hMSCs involves changes in the expression of epigenetically regulated genes, including imprinted genes, genes that contain CpG island in their TSS and chromatin related genes. Epigenetic de-regulation has been suggested to be a central effect of the aberrant expression of SYT-SSX and a possible mechanism underlying synovial sarcoma formation. The present transcriptome analysis of hMSC expressing SYT-SSX strongly supports this notion. Consistent with the variability of MSCSYT-SSX1 transcriptome relatedness to SS signatures and that of GO term overrepresentation, single population analysis limited to datasets of epigenetically regulated genes showed marked qualitative and quantitative differences among the four hMSC isolates, the most striking being the divergent effect of SYT-SSX on the expression of imprinted genes. It is therefore conceivable that epigenetic features displayed only by some hMSC populations permit SYT-SSX to affect expression of genes implicated in biological functions relevant to stem cells and SS. We therefore sought divergent epigenetic characteristics among the MSC populations that may explain the significant variations observed in the transcriptional effect of SYT-SSX. Assessment of the H19/IGF2 cluster provided support for our hypothesis. IGF2 is considered to be one of the signature genes of SS and is part of one of the best characterized imprinted clusters. Deregulation of its expression has been suggested to play a role in the development of several types of cancer. Real time PCR experiments revealed that different hMSC isolates display highly variable levels of IGF2 and H19 transcripts. Although a 273404-37-8 biological activity complex network of long range interactions and multiple looping are emerging as newly recognized regulators of H19 and IGF2, the methylation status at the H19 imprinting control region remains a basic regulatory factor according to the shared enhancer model. Bisulfite transformation analysis revealed a highly divergent methylation pattern among hMSC populations both at the H19 ICR and in a second region downstream of the H19 gene. In those populations that were found to be informative, the methylation pattern at the H19 ICR was shown to be compatible with maintenance or
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