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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050231-16
Application #
8496060
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Carter, Anthony D
Project Start
1995-05-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
16
Fiscal Year
2013
Total Cost
$300,601
Indirect Cost
$106,665
Name
Thomas Jefferson University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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
Fujioka, Miki; Yusibova, Galina L; Zhou, Jian et al. (2008) The DNA-binding Polycomb-group protein Pleiohomeotic maintains both active and repressed transcriptional states through a single site. Development 135:4131-9
Khan, F S; Fujioka, M; Datta, P et al. (2008) The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila. Cell Death Differ 15:1073-83
Petruk, Svetlana; Sedkov, Yurii; Riley, Kristen M et al. (2006) Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference. Cell 127:1209-21

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