Alan Michelson obtained his B.Sc. in biochemistry and biology from Dalhousie University in 1977 and his M.D. and Ph.D. from Harvard Medical School in 1986. His graduate work was undertaken in the laboratory of Stuart Orkin at Boston Children’s Hospital. Dr. Michelson also trained in internal medicine at Brigham and Women’s Hospital in Boston and did a postdoctoral fellowship in the laboratory of Tom Maniatis at Harvard University. In 2010 he received an individual NIH Director’s Award for innovative program development in genomics, systems biology, and stem cell research. Dr. Michelson has authored or coauthored more than 50 papers and is invited to speak regularly at conferences. He is on the editorial board of Developmental Biology, the official journal of the Society for Developmental Biology and is an elected member of the American Society for Clinical Investigation.
Dr. Michelson investigates the organization and activities of developmental gene regulatory networks using formation of the Drosophila embryonic heart and body wall muscles as a model system. His goal is to comprehensively identify and characterize the upstream regulators of cell fate specification, the downstream effectors of differentiation, and the complex interactions that occur among these components during organogenesis. His laboratory combines contemporary genome-wide experimental and computational approaches with classical genetics and embryology to generate mechanistic hypotheses that are then tested at single-cell resolution in the intact organism.
In prior studies, Dr. Michelson and his colleagues established that various tissue-restricted and signal-activated transcription factors direct the expression of individual genes in specific heart and muscle cells. They extended these findings by performing genome-wide expression profiling of wild-type and genetically perturbed mesodermal cells that were purified by flow cytometry, thereby identifying large numbers of co-expressed cardiogenic and myogenic genes. His current efforts are focused on identifying additional transcription factors that act in combination to govern the unique genetic programs of single cells during organogenesis.
Dr. Michelson is using cis- and trans- experimental approaches to examine the regulatory functions of candidate transcription factors identified in his expression profiling studies. He is also applying machine learning classifiers to characterize known muscle and heart enhancers based on the presence of shared sequence features. This computational strategy enables him to predict related regulatory elements on a genome-wide scale. In addition, the machine learning algorithm has identified a number of novel sequence motifs that are shared among known mesodermal enhancers and that are bound by different classes of transcription factors that have not previously been recognized as participating in muscle and heart gene regulatory networks.
In several cases, Dr. Michelson has obtained strong experimental evidence for the functional significance of newly identified transcription factors both in regulating distinct genes in specific cells and in governing broader developmental programs. For example, he has determined that a T-box transcription factor is essential for specifying the identities of individual myoblasts and that two Forkhead domain transcription factors control the division of cardiac progenitor cells.
In addition, he has obtained evidence that homeodomain transcription factors function through preferred DNA binding sites to regulate the cell type-specific activities of particular muscle transcriptional enhancers. Additional experiments are in progress to test gene regulatory models on a more global scale by using chromatin immunoprecipitation to determine the in vivo localization of various transcription factors and modified histones in chromatin isolated from purified Drosophila embryonic mesodermal cells.
Collectively, Dr. Michelson’s studies provide new insights into the combinatorial transcriptional codes that regulate heart and muscle gene expression, as well as into the specific developmental roles played by individual transcription factors in determining cellular identities and in controlling subsequent differentiation steps. These investigations also serve as an instructive experimental paradigm for investigating related questions in mammalian systems, where the knowledge obtained can guide the development of cell-based therapies and other approaches to regenerative medicine.