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Systems-level studies of glycosyltransferase gene expression and enzyme activity that are associated with the selectin binding function of human leukocytes

Dhananjay D. Marathe^*, E. V. Chandrasekaran, Joseph T. Y. Lau, Khushi L. Matta and Sriram Neelamegham^*,,1

^* Chemical and Biological Engineering and

New York State Center for Excellence in Bioinformatics and Life Sciences, State University of New York, Buffalo, New York, USA; and Departments of

Cancer Biology and

Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA

¹ Correspondence: 906 Furnas Hall, State University of New York at Buffalo, Buffalo, NY 14260, USA. E-mail: neel{at}eng.buffalo.edu

The application of systems biology methods in the emerging field of glycomics requires the collection and integration of glycosyltransferase data at the gene and enzyme level for the purpose of hypothesis generation. We systematically examined the relationship between gene expression, glycosyltransferase activity, glycan expression, and selectin-binding function in different systems, including human neutrophils, undifferentiated HL-60 (human promyelocytic cells), differentiated HL-60, and HL-60 synchronized in specific growth phases. Results demonstrate that 1) the sLe^X (sialyl-Lewis-X) epitope is expressed in P-selectin glycoprotein ligand-1 (PSGL-1) from neutrophils at higher levels compared with HL-60. This variation may be due to differences in the relative activities of 1,3-fucosyltransferases and 2,3-sialyltransferases in these two cell types. 2) HL-60 cell differentiation along granulocyte lineage increased the activity of β1,4GalT and β1,3GlcNAcT by 1.6- to 3.2-fold. This may contribute to LacNAc chain extension as evidenced by the 1.7-fold increase in DSA-lectin (lectin recognizing LacNAc) binding to cells after differentiation. 3) The activity of enzymes contributing to sLe^X formation in leukocytes likely varies as ST3[Galβ1,4GlcNAc] 1,3FT[sialyl-LacNAc] < β1,3GlcNAcT. 4) O-glycan specific glycosyltransferase activity does not undergo periodic variation with cell cycle phases. Overall, gene expression and enzyme activity data combined with knowledge of biochemistry can predict the resulting glycan structures and yield viable experimentally testable hypothesis.—Marathe, D. D., Chandrasekaran, E. V., Lau, J. T. Y., Matta, K. L., Neelamegham, S. Systems-level studies of glycosyltransferase gene expression and enzyme activity that are associated with the selectin binding function of human leukocytes.

Key Words: systems biology • glycan • PSGL-1 • inflammation • hydroxyurea