The long-term goal of this project is to uncover the role of the core promoter in the regulation of transcription by RNA polymerase II. The core promoter has been traditionally defined to be the sequences that direct the accurate initiation of transcription. However, this simple definition belies a complex and diverse component of the transcription process. Although the core promoter has historically been considered to be a somewhat generic and homogeneous moiety, it is now apparent that many different sequence motifs, such as the BREu, TATA, Inr, and DPE, can each confer specific transcriptional properties to the core promoter. There are no universal core promoter motifs. Moreover, in humans, the best known core promoter element, the TATA box, is present in only about 15% of promoters. It is thus likely that many more core promoter motifs remain to be discovered and characterized. The objective of the proposed research is to undertake a three-tiered approach to the study of the core promoter at the levels of DNA sequences, protein factors, and biological networks.
Specific Aim 1 focuses upon the discovery of new core promoter elements. At the present time, there is an incomplete understanding of the DNA sequences that direct the initiation of transcription by RNA polymerase II. There are new motifs as well as transcriptional strategies that remain to be uncovered.
Specific Aim 2 involves the identification and characterization of transcription factors that function in a core-promoter-specific manner. For example, Caudal is an enhancer-binding protein and master developmental regulator that functions as a DPE- specific activator. There are likely to be many other factors that regulate transcription via the core promoter.
Specific Aim 3 will explore the function of specific core promoter motifs in biological networks. For instance, the DPE is a central component of the Hox gene system. It is likely that other gene networks employ specific core promoter motifs in their regulation. In the future, the core promoter will be an integral part of all analyses of transcriptional regulation. A key aim of this grant is to provide new and important insights into the core promoter and thus contribute critical knowledge for understanding how genes are regulated.
These studies will lead to a better understanding of gene regulation, and will therefore provide new insights into the molecular basis and potential treatment of human diseases, such as many forms of cancer, that involve abnormalities in the control of the expression of genes
|Duttke, Sascha H C; Lacadie, Scott A; Ibrahim, Mahmoud M et al. (2015) Perspectives on Unidirectional versus Divergent Transcription. Mol Cell 60:348-9|
|Duttke, Sascha H C; Lacadie, Scott A; Ibrahim, Mahmoud M et al. (2015) Human promoters are intrinsically directional. Mol Cell 57:674-84|
|Duttke, Sascha H C (2015) Evolution and diversification of the basal transcription machinery. Trends Biochem Sci 40:127-9|
|Khuong, Mai T; Fei, Jia; Ishii, Haruhiko et al. (2015) Prenucleosomes and Active Chromatin. Cold Spring Harb Symp Quant Biol 80:65-72|
|Duttke, Sascha H C (2014) Meeting report: 11th EMBL conference on transcription and chromatin - August 23-26, 2014 - Heidelberg, Germany. Epigenetics 9:1317-21|
|Zehavi, Yonathan; Kuznetsov, Olga; Ovadia-Shochat, Avital et al. (2014) Core promoter functions in the regulation of gene expression of Drosophila dorsal target genes. J Biol Chem 289:11993-2004|
|Duttke, Sascha H C (2014) RNA polymerase III accurately initiates transcription from RNA polymerase II promoters in vitro. J Biol Chem 289:20396-404|
|Wang, Yuan-Liang; Duttke, Sascha H C; Chen, Kai et al. (2014) TRF2, but not TBP, mediates the transcription of ribosomal protein genes. Genes Dev 28:1550-5|
|Kedmi, Adi; Zehavi, Yonathan; Glick, Yair et al. (2014) Drosophila TRF2 is a preferential core promoter regulator. Genes Dev 28:2163-74|
|Duttke, Sascha H C; Doolittle, Russell F; Wang, Yuan-Liang et al. (2014) TRF2 and the evolution of the bilateria. Genes Dev 28:2071-6|
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