Ya-Lin Chiu, PhD
Assistant Investigator
Gladstone Institute of Virology and Immunology
Assistant Professor of Medicine
University of California, San Francisco
Email: ychiu@gladstone.ucsf.edu
Telephone: 415-734-4946
Fax: 415-355-0855

 
Areas of Investigation
My laboratory explores different aspects of RNA biology underlying the innate immunity acting against retrotransposition, the biological actions of RNA granules and miRNA-mediated gene regulation during viral pathogenesis. We have characterized the differing functions of two forms of APOBEC3G (A3G), an intrinsic antiretroviral factor and highlighted the unique roles of LMM and HMM A3G as cellular defenses against exogenous HIV and endogenous Alu retroelements respectively. We also demonstrated that RNA granules, macromolecular complexes responsible for translational regulation and RNA trafficking, are involved in the regulation of these dual physiological functions of A3G. We are currently exploring the interplays among RNA granules, A3G and related A3F enzymes, and Alu elements. Our goals are: (1) To study the intracellular signals and molecular interactions that govern the formation and disassembly of RNA granules and to decipher their potential roles in regulating the expression and antiviral activity of human A3G/A3F. (2) To explore how A3G/A3F-mediated recruitment of Alu into RNA granules regulates Alu retrotransposition and to assess how these interactions modulate the intrinsic antiviral activity of A3G/A3F.

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(3) To test the potential role of A3G/A3F in controlling Alu-mediated genomic instability and the contribution of such instability to the development of therapy-related leukemias and non-AIDS defined hematopoietic malignancies in HIV-positive patients occurring after genotoxic cancer therapy. We also plan to develop an A3G-independent line of investigation focused on molecular mechanisms underlying the miRNA-mediated gene expression of HIV and HCV pathogenesis, in particular during interferon treatment. Our goals are (1) To identify microRNAs whose expression substantially changed upon viral infection and/or interferon treatment. (2) To identify the viral RNA or human mRNA targets regulated by these microRNAs. (3) To explore the intrinsic physiological interplays among these microRNA regulatory pathways and their targeted human and viral genes during viral pathogenesis.

Approaches
We use a variety of molecular, biochemical, cell biological and immunological techniques to study the interplays among RNA granules, A3G and related A3F enzymes, and Alu elements. In brief, the common techniques include retroviral and lentiviral vector systems, HIV infection of primary T cells and T cell lines, genome-wide siRNA screening, FPLC, tandem affinity purification, flow cytometry, confocal microscopy, mass spectrometry, RNA electrophoretic mobility shift assays, and retrotransposition assays, etc. Biological systems currently include human T cell lines and peripheral blood-derived primary T cells and will expend to human hematopoietic stem cells and xenograft NOD/SCID mouse.

Contributions
Studies identifying APOBEC3G as a post-entry restriction factor for HIV in resting CD4 T cells (Nature 435:108–114, 2005).
Studies demonstrating that ABOBEC3G, in conjunction with RNA granules, functions to regulate endogenous mobile genetic elements (e.g., Alu RNAs), whose mobility contributes to a variety of human diseases including cancers and leukemias. (Proc. Natl. Acad. Sci. 103:15588-15593, 2006)
Studies revealing the regulation of APOBEC3G expression and complex formation in various primary immune cells. (J. Biol. Chem. 282:3589–3546, 2007.)

Some questions addressed in ongoing studies

• What intracellular signals and molecular interactions govern the formation and disassembly of RNA granules?
• What are their potential roles in regulating the expression and antiviral activity of A3G/A3F?
• How do RNA granules regulate the localization, translation, and stability of A3G and A3F mRNA?
• How do A3G/A3F enzymes recognize Alu RNA and exert its restricting effects?
• How do RNA granules and related cytoplasmic RNA structures, in conjunction with A3G/A3F, determine the intracellular trafficking and stability of Alu RNAs?
• Could levels of A3G and A3F vary in response to different types of cancer therapy?
• Could expression of A3G and A3F be increased sufficiently to overwhelm the aberrant Alu transcription and Alu retrotransposition after genotoxic cancer therapy?
• Could strategies to control aberrant Alu transcriptional activation and Alu retrotransposition suppress development of therapy-related leukemias after exposure to genotoxic stress?

Selected Recent Publications

1. Chiu YL and Greene WC. (2008). The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annual Review of Immunology 26:317–353.
2. Ellery PJ, Tippett E, Chiu YL, Paukovics G, Cameron PU, Solomon A, Lewin SR, Gorry PR, Jaworowski A, Greene WC, Sonza S and Crowe SM. (2007). The CD16+ monocyte subset is more permissive to infection and preferentially harbors HIV-1 in vivo. Journal of Immunology 178:6581–6589.
3. Stopak K, Chiu YL, Kropp J, Grant RM, and Greene WC. (2007). Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. Journal of Biological Chemistry 282: 3539–3546.
4. Chiu YL, Witkowska HE, Hall SV, Santiago M, Soros V, Esnault C, Heidmann T and Greene WC. (2006). High-Molecular-Mass APOBEC3G Complexes Restrict Alu Retrotransposition. Proceedings of the National Academy of Sciences USA 103: 15588–15593.
5. Chiu YL and Greene WC. (2006). Multifaceted antiviral actions of APOBEC3 cytidine deaminases. Trends in Immunology 27: 291–297.
6. Chiu YL, Soros V, Kreisberg J, Stopak K, Yonemoto W and Greene WC. (2005). Cellular APOBEC3G Restricts HIV-1 Infection in Resting CD4 T-cells. Nature 435: 108-114.