Genome-wide identification of modulators of transcriptional regulation in human B lymphocytes: the kinome meets the transcriptome

Most transcriptional interactions in the cell are modulated by a variety of genetic and epigenetic mechanisms, resulting in transcriptional networks that are both dynamic and context-dependent. However, current efforts to reverse-engineer these circuits have provided representations that are mostly static and limited to lower eukaryotes. In this talk we discuss MINDY (Modulator Inference by Network Dynamics), a new general method for the genome-wide discovery of post-translational modulators of transcriptional regulation processes in mammalian cells from large scale micorarray expression profile data. We first show that the method is effective in identifying signaling genes in the BCR pathway of human B cells, which is known to modulate the transcriptional profile of the MYC proto-oncogene. We then apply the method to the systematic identification of novel post-translational modulators of all transcription factors in human B cells that are active in normal, tumor related, and experimentally manipulated human B cells. Inferred modulators are highly enriched in kinases and transcription factors, recapitulate established regulation pathways, and identify novel post-translational regulators of transcriptional activity. Finally, we provide a genome-wide, all-against-all view of the kinome mediated modulation of the human transcriptome. The method is of broad applicability for the identification of cellular network dynamics in mammalian cells and for their comparison in normal and pathologic phenotypes.

Andrea Califano, PhD

Dr. Califano doctoral thesis in physics, at the University of Florence, was on the behavior of high dimensional dynamical systems. From 1986 to 1990, as a Research Staff Member in the Exploratory Computer Vision Group at the IBM TJ Watson Research Center he worked on several algorithms for machine learning, more specifically for the interpretation of 2D and 3D visual scenes. In 1990 Dr. Califano started his activities in Computational Biology and, in 1997, became the program director of the IBM Computational Biology Center, a worldwide organization active in several research areas related to bioinformatics, chemoinformatics, complex biological system modeling, simulation, microarray analysis, protein structure prediction, and molecular-dynamics. In 2000 he cofounded First Genetic Trust, Inc. to actively pursue translational genomics research and infrastructure related activities in the context of large-scale patient studies with a genetic components. In 2003, he was appointed Professor of Biomedical Informatics at Columbia University, where he is also director of the Columbia MAGNet center (one of the seven NIH Roadmap National Centers for Biomedical Computing), codirector of the Center for Computational Biology and Bioinformatics, and director of the Columbia Cancer Center Oncoinformatics core. His scientific interests lay in the investigation of complex biological systems using a variety of physics and knowledge based methods. Since 1998 he has been especially active in the development of integrative methodologies for cancer genetics research. He is the author of caWorkbench, an integrated genomics analysis platform which has been adopted by the NCI as part of the caBIG program. His current research activities focus on the reverse engineering, modeling, and simulation of mammalian cellular networks using information theoretic methods.