This proposal describes genetic and biochemical analyses of host factors regulating the expression of the Moloney murine leukemia virus, the prototype of the simple mammalian retroviruses. We are especially focused on characterizing the mechanism of action of specific factors that we have identified that limit or restrict virus expression in embryonic cell types. We will characterize the mechanisms by which murine embryonic stem (ES) cells transcriptionally silence proviral DNAs and maintain the integrity of the germ line. We will study three parallel pathways ? a rapid and highly efficient mechanism targeting a specific DNA element of the Moloney provirus, the tRNApro Primer Binding Site (PBS)? a less potent one acting at a conserved site, the negative control region (NCR) present on the proviral DNA of many retroviruses;? and a newly-identified one also acting broadly on many retroviruses. We will characterize the DNA-binding host proteins that mediate the silencing (ZFP809, YY1, and NP220) and determine how these silencing mechanisms are regulated so as to be specifically active in ES cells. The study will involve examination of ubiquitin ligases, SUMO transferases, and protein-protein interactions needed to form the large complex that binds to the viral DNA and induces silencing by making repressive histone modifications. We will also examine the mechanism by which one of these factors uniquely activates, rather than silences, one member of the retrovirus family (HTLV-1). Because the expression of retroviral DNAs is so closely correlated with expression of host genes during embryonic development, these experiments will provide important new information about the properties that define ?stemness? ? the pluripotent state of ES cells. These aspects of control of retroviruses by host factors will provide new targets for antiviral therapy. Most importantly, these experiments will significantly extend our understanding of fundamental aspects of retrovirus replication, and of new cell biological processes that impact on these important viruses.
The goal of this project is to expand our understanding of the Moloney murine leukemia virus ? prototype of the simple mammalian retroviruses, and a model for the human retroviruses HTLV-1 and HIV1 ? and of the host regulation of viral DNA expression. We are especially focused on characterizing the mechanism of action of specific host factors that we have identified that restrict virus expression in embryonic cell types. The work will reveal new aspects of the host machinery that can induce and maintain the latent status of integrated proviral DNAs and will inform new approaches to treatment of viral leukemias and AIDS.
|Cingöz, Oya; Goff, Stephen P (2018) Cyclin-dependent kinase activity is required for type I interferon production. Proc Natl Acad Sci U S A 115:E2950-E2959|
|Zhu, Yiping; Wang, Gary Z; Cingöz, Oya et al. (2018) NP220 mediates silencing of unintegrated retroviral DNA. Nature 564:278-282|
|Zhu, Yiping; Luo, Shukun; Sabo, Yosef et al. (2017) Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling. Cell Host Microbe 21:220-230|
|Goff, Stephen P (2017) Evolution: Zapping viral RNAs. Nature 550:46-47|
|Geis, Franziska K; Galla, Melanie; Hoffmann, Dirk et al. (2017) Potent and reversible lentiviral vector restriction in murine induced pluripotent stem cells. Retrovirology 14:34|
|Wang, Cheng; Goff, Stephen P (2017) Differential control of retrovirus silencing in embryonic cells by proteasomal regulation of the ZFP809 retroviral repressor. Proc Natl Acad Sci U S A 114:E922-E930|
|Wang, Gary Z; Goff, Stephen P (2017) Transcriptional Silencing of Moloney Murine Leukemia Virus in Human Embryonic Carcinoma Cells. J Virol 91:|
|Tang, Xuhua; Zhu, Yiping; Baker, Stacey L et al. (2016) Structural basis of suppression of host translation termination by Moloney Murine Leukemia Virus. Nat Commun 7:12070|
|Wang, Gary Z; Wang, Ying; Goff, Stephen P (2016) Histones Are Rapidly Loaded onto Unintegrated Retroviral DNAs Soon after Nuclear Entry. Cell Host Microbe 20:798-809|
|Yang, Bin Xia; El Farran, Chadi A; Guo, Hong Chao et al. (2015) Systematic identification of factors for provirus silencing in embryonic stem cells. Cell 163:230-45|
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