Changes in gene transcription are important in the progression of cancer, in most other human diseases, and in the aging process, as well as in the development of multicellular organisms at all stages. A detailed understanding of how such changes are regulated is the basis of both diagnostic tools and intervention strategies. Further advancement holds the promise of novel approaches, and of increased effectiveness of current approaches. Importantly, many questions remain about the fundamental processes involved. Tools available in Drosophila make it possible to study mechanisms of action and interaction in detail, in a true in vivo context. This proposal is to study mechanisms of chromatin-based gene regulation involving Polycomb- response elements and an insulator, recently discovered in the well-characterized Drosophila gene even skipped. These studies will address basic questions of how transcriptional memory and chromosome organization work in 3 dimensions in the nucleus. They will provide a clearer understanding of how epigenetic mechanisms propagate alternative transcriptional states, and the importance of long-range regulatory interactions between distant genomic regions. In mammals, Polycomb Group proteins are involved in maintenance of the stem cell niche, and in oncogenesis. Therefore, these studies will have direct applications to research on human diseases.
The Specific Aims are: 1) to investigate mechanisms of maintenance of repression and activation by Polycomb- response elements from the even-skipped locus 2) to study mechanisms of long-range insulator-mediated enhancer-promoter communication, and 3) to test the properties and functions of even-skipped Polycomb-response elements and the insulator in their native context.
Changes in gene transcription are important in the progression of cancer, in most other human diseases, and in the aging process, as well as in the development of multicellular organisms at all stages. A detailed understanding of how such changes are regulated is the basis of both diagnostic tools and intervention strategies, and is the general subject of this proposal. Further advancement holds the promise of novel approaches, and of increased effectiveness of current approaches.
|Chetverina, Darya; Fujioka, Miki; Erokhin, Maksim et al. (2017) Boundaries of loop domains (insulators): Determinants of chromosome form and function in multicellular eukaryotes. Bioessays 39:|
|Peacock, Jacob; Jaynes, James B (2017) Using competition assays to quantitatively model cooperative binding by transcription factors and other ligands. Biochim Biophys Acta 1861:2789-2801|
|Fujioka, Miki; Mistry, Hemlata; Schedl, Paul et al. (2016) Determinants of Chromosome Architecture: Insulator Pairing in cis and in trans. PLoS Genet 12:e1005889|
|Lacin, Haluk; Rusch, Jannette; Yeh, Raymond T et al. (2014) Genome-wide identification of Drosophila Hb9 targets reveals a pivotal role in directing the transcriptome within eight neuronal lineages, including activation of nitric oxide synthase and Fd59a/Fox-D. Dev Biol 388:117-33|
|Fujioka, Miki; Sun, Guizhi; Jaynes, James B (2013) The Drosophila eve insulator Homie promotes eve expression and protects the adjacent gene from repression by polycomb spreading. PLoS Genet 9:e1003883|
|Fujioka, Miki; Jaynes, James B (2012) Regulation of a duplicated locus: Drosophila sloppy paired is replete with functionally overlapping enhancers. Dev Biol 362:309-19|
|Fujioka, Miki; Gebelein, Brian; Cofer, Zenobia C et al. (2012) Engrailed cooperates directly with Extradenticle and Homothorax on a distinct class of homeodomain binding sites to repress sloppy paired. Dev Biol 366:382-92|
|Johnston, Danika M; Sedkov, Yurii; Petruk, Svetlana et al. (2011) Ecdysone- and NO-mediated gene regulation by competing EcR/Usp and E75A nuclear receptors during Drosophila development. Mol Cell 44:51-61|
|Prazak, Lisa; Fujioka, Miki; Gergen, J Peter (2010) Non-additive interactions involving two distinct elements mediate sloppy-paired regulation by pair-rule transcription factors. Dev Biol 344:1048-59|
|Fujioka, Miki; Wu, Xian; Jaynes, James B (2009) A chromatin insulator mediates transgene homing and very long-range enhancer-promoter communication. Development 136:3077-87|
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