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The role of TLS, EWS and TAF15 in erroneous gene regulation and cancer

Kristi Fox-Walsh

Appointment Period: 2008-2010 / Grant Years: [24,25]

Kristi Fox-WalshTLS was first discovered as the fusion gene TLS-CHOP within myxoid liposarcomas, but is also an indicator for other cancers. Strikingly, 90% of myxoid liposarcomas contain the TLS/CHOP fusion protein. Additionally, the two other members of the TET family of proteins, EWS and TAF15 have been shown to create fusion proteins associated with the occurrence of Ewing’s Sarcoma and leukemia, respectively. We hypothesize that these proteins may be working in a similar manner and regulating many of the same genes to function as oncoproteins when they are fused with another gene. To test this hypothesis I have proposed to examine the role of TLS, EWS and TAF15 using genome-wide analyses to further understand how the fusion of these genes and miss-regulation may cause cancer.

Over the past year, I have optimized siRNA-mediated knockdown of TLS, EWS, TAF15, and the TLS interacting non-coding RNA for greater than 85% knockdown in order to examine gene specific expression changes. Using RNA-seq technology I have identified a number of genes altered after knockdown, and have validated a portion of these genes. Three replicates were deep sequenced for each knockdown condition and are in the process of being analyzed to examine regulated gene expression. The CLIP data along with the RNA-seq expression analysis and PolII Chip provide a platform for understanding the global affect of TLS, EWS and TAF15 on transcription and gene regulation. We are confident this work will help to elucidate the function of TLS, EWS and TAF15 in cancer, and more specifically, liposarcomas, Ewing sarcomas and leukemia.

Fox-Walsh KL, Hertel KJ. Splice-site pairing is an intrinsically high fidelity process. Proc Natl Acad Sci USA. (2009) 106:1766-71. PMID: 19179398; PMC2644112.

Fox-Walsh K, Fu XD. Chromatin: the final frontier in splicing regulation? Dev Cell. (2010) 18:336-8. PMID: 20230741.

Fox-Walsh K, Davis-Turak J, Zhou Y, Li H, Fu XD. A multiplex RNA-seq strategy to profile poly(A+) RNA: application to analysis of transcription response and 3' end formation. Genomics. (2011) 98:266-71. PMID: 21515359; PMCID: PMC3160523.