Iws1 (Interacts with Spt6) was originally identified in the yeast Saccharomyces Cerevisciae as a binding partner of Spt6, a histone H3/H4 chaperone. Spt6 also binds the C terminal domain (CTD) of the large subunit of RNA Pol II, following the phosphorylation of the latter at Ser2. Recent studies in mammalian cells revealed that the Spt6/Iws1 complex assembled on the CTD of RNA Pol II, contains two additional members, Aly/REF, an adaptor that contributes to nucleocytoplasmic RNA transport, and SetD2, a histone H3K36 trimethyl- transferase. The same studies showed that this complex contributes to alternative RNA splicing. Work in the Tsichlis laboratory extended these observations by showing that the recruitment of SetD2 to the Iws1 complex and the trimethylation of histone H3 at K36 during transcriptional elongation depend on the phosphorylation of Iws1 by Akt1 and Akt3. More important, the Akt-dependent H3K36 trimethylation in transcriptionally active genes regulates alternative RNA splicing and contributes to the biology of human non-small cell lung carcinomas (NSCLCs). More recent studies in the Tsichlis laboratory produced evidence that Iws1 may regulate not only RNA splicing, but also other steps in RNA metabolism. In addition, it may play an important role in the development and biology of tumors other than NSCLCs, including mammary adenocarcinomas and melanomas. It is noteworthy that the role of IWS1 in mammary adenocarcinomas is also supported by large scale data from primary human tumors in the TCGA database. Addressing some of the questions arising from these findings required the establishment of a mouse genetic model. This was accomplished by Dr Coppola who established a conditional Iws1 knockout mouse. Using this mouse, the Tsichlis and Coppola laboratories will address 1) the physiological role of Iws1 in embryonic development and in the biology of adult animal tissues; 2) the role of Iws1 in oncogenesis; and 3) the molecular mechanisms by which Iws1 regulates RNA metabolism and other cellular functions.

Public Health Relevance

Recent studies by us and others revealed a strong link between RNA metabolism and human cancer. However, our mechanistic understanding of this link is limited. In this application, the Tsichlis and Coppola laboratories are focusing on this problem, by exploring the function of the transcription elongation factor Iws1, which based on data from the Tsichlis laboratory, plays an important role in human cancer. The establishment of a conditional Iws1 knockout mouse model by Dr. Coppola provides an excellent opportunity for the two laboratories to combine their assets and expertise to effectively address this problem.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Strasburger, Jennifer
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Ohio State University
Schools of Medicine
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Orlacchio, Arturo; Stark, Aaron E; Foray, Claudia et al. (2018) Genetic ablation of interacting with Spt6 (Iws1) causes early embryonic lethality. PLoS One 13:e0201030
McNiel, Elizabeth A; Tsichlis, Philip N (2017) Analyses of publicly available genomics resources define FGF-2-expressing bladder carcinomas as EMT-prone, proliferative tumors with low mutation rates and high expression of CTLA-4, PD-1 and PD-L1. Signal Transduct Target Ther 2:
Voulgarelis, Michael; Tsichlis, Philip N (2016) Proline hydroxylation linked to Akt activation. Science 353:870-1