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.

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041249-25
Application #
8387752
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Sledjeski, Darren D
Project Start
1988-12-01
Project End
2013-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
25
Fiscal Year
2013
Total Cost
$325,080
Indirect Cost
$110,126
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Duttke, Sascha H C (2014) RNA polymerase III accurately initiates transcription from RNA polymerase II promoters in vitro. J Biol Chem 289:20396-404
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
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
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
Cianfrocco, Michael A; Kassavetis, George A; Grob, Patricia et al. (2013) Human TFIID binds to core promoter DNA in a reorganized structural state. Cell 152:120-31
Theisen, Joshua W M; Gucwa, James S; Yusufzai, Timur et al. (2013) Biochemical analysis of histone deacetylase-independent transcriptional repression by MeCP2. J Biol Chem 288:7096-104
Juven-Gershon, Tamar; Kadonaga, James T (2010) Regulation of gene expression via the core promoter and the basal transcriptional machinery. Dev Biol 339:225-9
Parry, Trevor J; Theisen, Joshua W M; Hsu, Jer-Yuan et al. (2010) The TCT motif, a key component of an RNA polymerase II transcription system for the translational machinery. Genes Dev 24:2013-8
Theisen, Joshua W M; Lim, Chin Yan; Kadonaga, James T (2010) Three key subregions contribute to the function of the downstream RNA polymerase II core promoter. Mol Cell Biol 30:3471-9

Showing the most recent 10 out of 13 publications