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Ram Savan, Ph.D.
Ram Savan, Ph.D.
Assistant Professor, Immunology
Dr. Ram Savan received his Ph.D. in 2004 from Kagoshima University in Japan. He completed postdoctoral training in the Laboratory of Experimental Immunology at the National Cancer Institute in 2011. He joined the Department of Immunology as an Assistant Professor in 2011.
Department of Immunology
University of Washington
Office E307, Box 358059
750 Republican Street
Seattle WA 98109-8059
Our laboratory investigates the regulation of immune genes and its impact on infection and autoimmunity, with specific interests in identifying post-transcriptional regulators of innate immune effectors that include RNA binding proteins and non-coding RNAs.
There are several regulatory mechanisms that have evolved to regulate gene expression via the 3′ untranslated region (3′ UTR). Many interferon and cytokine genes are regulated by cis-acting repetitive adenosine-uridine stretches (AUUUA), referred to as AU-rich elements (ARE) that destabilize the mRNA through an ARE-mediated decay (AMD) process. The ARE regions are targeted by RNA-binding proteins for degradation and/or stabilization. Majority of cytokine genes harbor ARE motifs in their 3′ UTR and are known to be regulated by AMD. In addition to the ARE elements in the 3′ UTRs, target sites for microRNA (miRNA) binding have also been identified. miRNAs are endogenous, single stranded RNA molecules 21-23 nucleotides in length and have emerged as potent regulators of gene expression that can inhibit translation of proteins in mammals through the miRNA-induced silencing complex (miRISC). As testament to their importance, 30 % of all genes are known to be regulated by miRISC. We and others have shown that miRISC and ARE-binding proteins interact to control gene dosage. Another level of post-transcriptional regulation occurs via shortening of the 3′ UTR in order to escape RNA binding proteins and/or miRNA-mediated regulation. Additionally, as immune genes are under positive selection, these genes adapt to host and environmental pressures by varying their expression, often to protect the host against infection. One method of adaptation involves polymorphisms in the 3′ UTR, which alter the targeting of RNA-binding proteins and miRNAs.
These mechanisms of post-transcription regulation, and their effect on the immune response, are just beginning to be understood. Although individual miRNA:gene interactions are important, they do not adequately represent the full complexity of regulatory events. Our laboratory is focused on understanding the complexity of these pathways by coupling robust computational approaches with functional studies.
- Jarret A, McFarland AP, Horner SM, Kell A, Schwerk J, Hong M, Badil S, Joslyn RC, Baker DP, Carrington M, Hagedorn CH, Gale M Jr, Savan R. Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nat Med. 2016 Dec;22(12):1475-1481. doi: 10.1038/nm.4211.
- Hong M, Schwerk J, Lim C, Kell A, Jarret A, Pangallo J, Loo YM, Liu S, Hagedorn CH, Gale M Jr, Savan R. Interferon lambda 4 expression is suppressed by the host during viral infection. J Exp Med. 2016 Nov 14;213(12):2539-2552.
- Lim C, Hong M, Savan R. Human IL-22 binding protein isoforms act as a rheostat for IL-22 signaling. Sci Signal. 2016 Sep 27;9(447):ra95. doi:10.1126/scisignal.aad9887.
- Schwerk J, Savan R. Translating the Untranslated Region. J Immunol. 2015 Oct1;195(7):2963-71. doi: 10.4049/jimmunol.1500756. Review.
- Schwerk J, Jarret AP, Joslyn RC, Savan R. Landscape of post-transcriptional gene regulation during hepatitis C virus infection. Curr Opin Virol. 2015 Jun;12:75-84. doi: 10.1016/j.coviro.2015.02.006. Review.
- Steinhagen F, McFarland AP, Rodriguez LG, Tewary P, Jarret A, Savan R, Klinman DM. IRF-5 and NF-κB p50 co-regulate IFN-β and IL-6 expression in TLR9-stimulated human plasmacytoid dendritic cells. Eur J Immunol. 2013 Jul;43(7):1896-906. doi: 10.1002/eji.201242792.
- Kulkarni S, Savan R, Qi Y, Gao X, Yuki Y, Bass SE, Martin MP, Hunt P, Deeks SG, Telenti A, Pereyra F, Goldstein D, Wolinsky S, Walker B, Young HA, Carrington M. Differential microRNA regulation of HLA-C expression and its association with HIV control. Nature. 2011 Apr 28;472(7344):495-8. doi: 10.1038/nature09914.
- Savan R. Post-transcriptional regulation of interferons and their signaling pathways. J Interferon Cytokine Res. 2014 May;34(5):318-29. doi: 10.1089/jir.2013.0117. Review.
- McFarland AP, Horner SM, Jarret A, Joslyn RC, Bindewald E, Shapiro BA, Delker DA, Hagedorn CH, Carrington M, Gale M Jr, Savan R. The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs. Nat Immunol. 2014 Jan;15(1):72-9. doi: 10.1038/ni.2758.
Ph.D., United Graduate School of Agriculture Sciences, Kagoshima University, Japan