Iws1, an RNA-polymerase II (RNAPII)-associated transcription elongation factor, plays crucial roles in multiple biological processes. It is involved in histone modification, pre-mRNA splicing, and mRNA export pathways. Iws1 interacts with Spt6, a histone H3 chaperone, and recruits the lysine methyltransferase Setd2 to chromatin to regulate H3K36me3, which is important for pre-mRNA splicing [2,4].

Genetic ablation of Iws1 in mice leads to early embryonic lethality at the pre-implantation stage, highlighting its essentiality for mouse embryonic development [5]. In Toxoplasma gondii, Iws1-deficient parasites show decreased ROP18 mRNA expression, increased loading of IFN-inducible GTPases onto the parasitophorous vacuole membrane, and reduced virulence in wild-type mice, indicating its role in parasite fitness within IFN-γ-activated host cells [1]. In liposarcoma, AKT-mediated phosphorylation of Iws1 promotes the maintenance of cancer stem cells, mesenchymal-epithelial plasticity, and tumor metastasis, with Iws1 expression associated with poor patient prognosis [3].

In summary, Iws1 is essential for mouse embryonic development and has significant implications in disease-related processes such as parasite-host interactions and cancer progression. Gene knockout models in mice have been instrumental in revealing these functions, providing insights into potential therapeutic targets for diseases like liposarcoma and understanding the mechanisms of parasite survival in host cells.

References:

1. Hashizaki, Emi, Sasai, Miwa, Okuzaki, Daisuke, Iwanaga, Shiroh, Yamamoto, Masahiro. 2023. Toxoplasma IWS1 Determines Fitness in Interferon-γ-Activated Host Cells and Mice by Indirectly Regulating ROP18 mRNA Expression. In mBio, 14, e0325622. doi:10.1128/mbio.03256-22. https://pubmed.ncbi.nlm.nih.gov/36715543/

2. Oqani, Reza K, Lin, Tao, Lee, Jae Eun, Shin, Hyun Young, Il Jin, Dong. 2019. Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation. In Scientific reports, 9, 3831. doi:10.1038/s41598-019-40358-3. https://pubmed.ncbi.nlm.nih.gov/30846735/

3. Wang, Yu, Zhang, Hongji, La Ferlita, Alessandro, Pollock, Raphael E, Beane, Joal D. 2023. Phosphorylation of IWS1 by AKT maintains liposarcoma tumor heterogeneity through preservation of cancer stem cell phenotypes and mesenchymal-epithelial plasticity. In Oncogenesis, 12, 30. doi:10.1038/s41389-023-00469-z. https://pubmed.ncbi.nlm.nih.gov/37237004/

4. Yoh, Sunnie M, Lucas, Joseph S, Jones, Katherine A. . The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. In Genes & development, 22, 3422-34. doi:10.1101/gad.1720008. https://pubmed.ncbi.nlm.nih.gov/19141475/

5. Orlacchio, Arturo, Stark, Aaron E, Foray, Claudia, Tsichlis, Philip N, Coppola, Vincenzo. 2018. Genetic ablation of interacting with Spt6 (Iws1) causes early embryonic lethality. In PloS one, 13, e0201030. doi:10.1371/journal.pone.0201030. https://pubmed.ncbi.nlm.nih.gov/30208029/