Gradients of cell signaling molecules and regulatory factors are pervasively used in a variety of patterning process in metazoan development. Examples include the Sonic Hedgehog gradient that specifies different neuronal cell types in the neural tube of vertebrate embryos, and the Dpp gradient that patterns the developing wing imaginal disk in Drosophila larvae. The Toll-Dorsal signaling pathway represents one of the most thoroughly characterized gradient systems in animal development. The proposed study represents a continuation of our efforts to determine how the Dorsal regulatory gradient produces multiple thresholds of gene expression and tissue differentiation in the early Drosophila embryo. The research plan includes 3 specific aims. First, we will examine the activities of Dorsal target genes that were identified in recent whole-genome microarray assays. Among the newly identified genes that will be tested is Eiger, the major TNF homolog in the Drosophila genome, and Mes4, which encodes a tissue-specific subunit of the CACAAT-box binding protein complex, NF-Y. Second, we will use a combination of bioinformatics methods and transgenic assays to determine how the Dorsal gradient regulates the expression of different target genes in a concentration-dependent manner. Particular efforts will focus on defining a """"""""cis-regulatory code"""""""", whereby coordinately regulated target enhancers share a characteristic combination of factor binding sites, including binding sites for Dorsal and additional, mainly unknown regulatory factors. Third, we will determine whether immunity genes that are induced upon infection or injury share a similar organization of cis-regulatory elements. Particular efforts will focus on genes that are activated by the Dorsal-related immunity genes, Dif and Relish, and the GATA transcription factor, Serpent.
| Lim, Bomyi; Levine, Michael; Yamazaki, Yuji (2017) Transcriptional Pre-patterning of Drosophila Gastrulation. Curr Biol 27:286-290 |
| Esposito, Emilia; Lim, Bomyi; Guessous, Ghita et al. (2016) Mitosis-associated repression in development. Genes Dev 30:1503-8 |
| Fukaya, Takashi; Lim, Bomyi; Levine, Michael (2016) Enhancer Control of Transcriptional Bursting. Cell 166:358-368 |
| Farley, Emma K; Olson, Katrina M; Zhang, Wei et al. (2015) Suboptimization of developmental enhancers. Science 350:325-8 |
| Farley, Emma K; Olson, Katrina M; Levine, Michael S (2015) Regulatory Principles Governing Tissue Specificity of Developmental Enhancers. Cold Spring Harb Symp Quant Biol 80:27-32 |
| Levine, Michael; Cattoglio, Claudia; Tjian, Robert (2014) Looping back to leap forward: transcription enters a new era. Cell 157:13-25 |
| Levine, Michael (2014) The contraction of time and space in remote chromosomal interactions. Cell 158:243-244 |
| Lagha, Mounia; Bothma, Jacques P; Esposito, Emilia et al. (2013) Paused Pol II coordinates tissue morphogenesis in the Drosophila embryo. Cell 153:976-87 |
| Boettiger, Alistair Nicol; Levine, Michael (2013) Rapid transcription fosters coordinate snail expression in the Drosophila embryo. Cell Rep 3:8-15 |
| Chopra, Vivek S; Kong, Nikki; Levine, Michael (2012) Transcriptional repression via antilooping in the Drosophila embryo. Proc Natl Acad Sci U S A 109:9460-4 |
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