Faculty and Research
Faculty by Name
Michael Levine
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Michael Levine
Professor of Genetics, Genomics and Development*
*And Affiliate, Division of Cell and Developmental Biology
Research Interests
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My lab studies gene networks that control animal development and disease. Research focuses largely on how noncoding regions of the genome function to control the differential patterns of gene expression, both spatial and temporal, that define cell behavior. The developmental stage of multicellular organisms in particular requires very explicit control of gene expression in order to layout different cell tissue types. Using model developmental systems, including the early Drosophila embyro, the sea squirt, Ciona intestinalis, and the flour beetle, Tribolium castaneum, we are working to develop a deeper understanding of genetic regulatory codes.
Current Projects
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Whole genome CHiP-chip analysis of the RNA polymerase II DNA binding in the early Drosophila embryo revealed that many of the spatially patterned regulatory genes load polymerase to the promoter and initiate transcription independent of enhancer activity. Enhancer loading by the appropriate activating factors is required for transcription to proceed past promoter-proximal region, but not polymerase binding. We are investigating the molecular mechanisms involved in this form of regulation and its biological consequences for gene regulation.
Similar CHiP-chip experiments for the primary Dorsal-ventral patterning transcription factors, Dorsal, Twist and Snail revealed novel DV enhancer elements. From these experiments, we have been able to show that some genes have multiple enhancers--secondary “shadow enhancers” located in more distal regions which drive the same pattern as the originally discovered primary enhancers. We are investigating the evolutionary context of these multiple enhancers by probing how they change across different Drosophilid and other insect species. We are also investigating the possible functional roles of these duplicate elements in the control of developmental patterning.One of the most amazing properties of developmental patterning systems is their reliability and robustness to perturbation. Despite the stochastic nature of the underlying reactions that control development, the whole process exhibits precise spatial regulation on the level of single cells separated by mere microns and surprising temporal coordination. We have developed quantitative population based assays to measure natural variability in the temporal and spatial expression patterns of individual genes, between cells in the same embryo and between different embryos of the same age. With this methods we have recently shown that genes which regulate the initiation step of transcription are activated in a much more stochastic fashion than the elongation regulated genes. We are adapting these methods to gain new insights into the reliability and robustness of Drosophila embryonic patterning.
The sea squirt, Ciona intestinalis, is a simple chordate with a small genome that has been recently sequenced and assembled. The Ciona genome represents a simplified version of vertebrate genomes. The Ciona tadpole is initially composed of just ~1,000 cells and there is complete lineage information. It is possible to introduce transgenic DNAs into developing embryos using simple electroporation methods. A provisional circuit diagram is now available for the specification of the major larval tissues during the 32- and 110-cell stages of embryogenesis. This diagram provides a foundation for understanding the differentiation of key organs such as the notochord and heart. We are now using a combination of confocal imaging, cell sorting, and microarray assays to identify the genes and gene interactions responsible for the migration and differentiation of the heart precursor cells.
Selected Publications
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Boettiger AN, Levine M. (2009) Transcriptional synchrony in the early Drosophila embryo. Science. In press.
Chopra VS, Cande J, Hong JW, Levine M. (2009) Stalled Hox promoters as chromosomal boundaries. Genes and Dev. 23(13):1505-9.
Pubmed
Chopra VS, Hong JW, Levine M. (2009) Regulation of Hox Gene Activity by Transcriptional Elongation in Drosophila. Curr. Biol. 19(8):688-93
Pubmed
Goltsev Y, Rezende GL, Vranizan K, Lanzaro G, Valle D, Levine M. (2009) Developmental and evolutionary basis for drought tolerance of the Anopheles gambiae embryo. Dev Biol.
Pubmed
Shi W, Hendrix D, Levine M, and Haley B. (2009) A distinct class of small RNAs arises from pre-miRNA-proximal regions in a simple chordate. Nature Struct Mol Biol. 16:183-9.
Pubmed
Imai KS, Stolfi A, Levine M, Satou Y. (2009) Gene regulatory networks underlying the compartmentalization of the Ciona central nervous system. Development 136(2):285-93
Pubmed
Shi W, Peyrot SM, Munro E, Levine M. (2009) FGF3 in the floor plate directs notochord convergent extension in the Ciona tadpole. Development 136(1):23-8
Pubmed
Hong JW, Hendrix DA, Levine MS. (2008) Shadow enhancers as a source of evolutionary novelty. Science. 321:1314.
Pubmed
Last Updated 2009-07-08