Study of Ribonucleic Acid (http://rnamodifications.org)

RNAs deliver a diverse spectrum of biological functions in nature not only through their sequences of four canonical nucleosides (A, C, G and U), but also through their hundreds of types of structural modifications. Many RNA modifications are directly or indirectly linked with human diseases such as cancer, neurological disorders and autoimmune diseases. Given the supreme importance of the RNA modifications in human biology, we aspire to pursue their structural diversity and the mechanistic underpinnings of modification-driven regulation and functions. Our research will also answer the longstanding questions of: 1) how these RNA modifications interact with one another to deliver a broad scope of controlled biological functions and intricate regulation, and 2) how the level of RNA modifications changes in response to changes in cellular environment and environmental stress. Our rigorous pursuit of new structures and functions related to RNA modifications will not only provide new perspectives into the study of RNA epigenetic regulations, but will also facilitate the identification of new RNA biomarkers and targets for drug discovery and personalized medicine.

Recent Projects/Research:

• Methodological development for the direct sequencing of RNAs and their modifications.
• Development of facile and robust strategies for the synthetic preparation of non-canonical ribonucleosides and their incorporations into RNA.
• Probing the breadth of regulatory roles of RNA modifications in gene expression and RNA modifications as biomarkers for diagnosis.
• Systems-level mapping of the roles of RNA modifications, and the modifications’ interactions with other cellular components, into a holistic regulatory network.

Selected Publications:

• Wang R, Luo Z, Shen F, Liu H, Zhang S, Gan J, Sheng J. Structural insights into RNA duplexes with multiple 2′-5′-linkages. Nucleic Acids Research, 2017, 45 (6): 3537-3546.
• Björkbom A*, Lelyveld VS*, Zhang S *, Zhang W, Tam CP, Blain JC, Szostak JW. Bidirectional direct sequencing of non-canonical RNA by two-dimensional analysis of mass chromatograms. J Am Chem Soc., 2015, DOI: 10.1021/jacs.5b09438.
• Zhang S, Blain JC, Zielinska D, Gryaznov SM, Szostak JW. Fast and Accurate Non-enzymatic Copying of an RNA-like Synthetic Genetic Polymer. Proc Natl Acad Sci USA., 2013, 110(44): 17732-17737 (This work was highlighted in Proc Natl Acad Sci USA., 2013, 110(44): 17601-17602; and was featured as a research highlight in Nature Chemistry, 2013, 5: 984-985)
• Zhang S, Zhang N, Blain JC, Szostak JW. Synthesis of N3´-P5´-linked Phosphoramidate DNA by Non-enzymatic Template-directed Primer Extension. J Am Chem Soc., 2013, 135 (2): 924-932
• Zhang N, Zhang S, Szostak JW. Activated Ribonucleotides Undergo a Sugar Pucker Switch upon Binding to a Single-Stranded RNA Template. J Am Chem Soc., 2012, 134 (8): 3691–3694
• Guo J, Xu N, Li Z, Zhang S, Wu J, Kim DH, Marma MS, Meng Q, Cao H, Li X, Shi S, Yu L, Kalachikov S, Russo JJ, Turro NJ, Ju J. Four-color DNA Sequencing with 3´-O-modified Nucleotide Reversible Terminators and Cleavable Fluorophore-modified Dideoxynucleotides. Proc Natl Acad Sci USA., 2008, 105(27): 9145-9150
• Wu J, Zhang S, Meng Q, Cao H, Li Z, Li X, Shi S, Kim DH, Bi L, Turro NJ, Ju J. 3´-O-labeled Reversible Terminators for Pyrosequencing. Proc Natl Acad Sci USA., 2007, 104(42): 16462-16467

Patent:

• WO 2009051807 2009: Design and synthesis of labile azido linkers for conjugation of fluorescent dyes to nucleotides for use as reversible terminators in DNA sequencing by synthesis