The RNA polymerase II core promoter is a structurally and functionally diverse regulatory element that lies at the center of the transcription process. For instance, the presence or absence of a specific core promoter motif, such as the TATA or DPE, can be required for the proper regulation of a gene. Notably, the lack of sufficient knowledge of the core promoter is a critical limiting factor in the understanding of transcriptional regulatory mechanisms. The proposed research is designed to advance the analysis of eukaryotic transcription in important new directions. One key area is the study of the TRF2-based transcription system, particularly in conjunction with the TCT core promoter motif. TRF2 (TBP-related factor 2) is conserved among metazoans, but unlike TBP (TATA box-binding protein), TRF2 does not bind to the TATA box. Transcription of TATA-less TCT-dependent core promoters (nearly all core promoters that contain the TCT motif are TATA-less) requires TRF2 but not TBP. Notably, purified TRF2 functions as a transcription factor on TCT-dependent promoters in vitro. It thus appears that there is a TRF2-based transcription system that is distinct from the well-known TBP/TFIID-based transcription system.
Specific Aim 1 seeks to determine the composition of TRF2 complexes and to analyze the functions of TRF2 and TRF2-associated proteins via cell- based and genetic approaches.
Specific Aim 2 proposes to identify TCT-specific basal transcription factors that are required, in addition to TRF2, for TCT-dependent transcription. The analysis of the factors that constitute the TRF2-based transcription system would be an important contribution to transcription. Moreover, some TRF2-associated proteins and TCT- specific basal factors may serve as a link to the regulation of the ribosomal protein gene network. This proposal also seeks to expand the knowledge of the core promoter itself.
Specific Aim 3 is directed toward the exploration and discovery of new core promoter motifs. The proposed studies in this grant should provide valuable new information on novel transcription systems as well as new core promoter motifs and types. Principal Investigator: Kadonaga, James T. 2R01 GM041249-26 2.
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.
|Vo Ngoc, Long; Cassidy, California Jack; Huang, Cassidy Yunjing et al. (2017) The human initiator is a distinct and abundant element that is precisely positioned in focused core promoters. Genes Dev 31:6-11|
|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; Lacadie, Scott A; Ibrahim, Mahmoud M et al. (2015) Perspectives on Unidirectional versus Divergent Transcription. Mol Cell 60:348-9|
|Duttke, Sascha H C (2015) Evolution and diversification of the basal transcription machinery. Trends Biochem Sci 40:127-9|
|Duttke, Sascha H C; Lacadie, Scott A; Ibrahim, Mahmoud M et al. (2015) Human promoters are intrinsically directional. Mol Cell 57:674-684|
|Duttke, Sascha H C (2014) Meeting report: 11th EMBL conference on transcription and chromatin - August 23-26, 2014 - Heidelberg, Germany. Epigenetics 9:1317-21|
|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|
|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|
|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|
Showing the most recent 10 out of 21 publications