Shinako Takada, Ph.D.

Regulation of gene expression is fundamental for all aspects of biological processes. Our laboratory uses biochemical approaches and molecular biology to study the mechanisms by which transcription, the first regulated step in gene expression, is controlled. Eukaryotic transcription is regulated by a complex network of interactions among factors that include the basal transcription machinery (the RNA polymerase II and the general transcription factors), gene-specific transcription regulators and co-regulators, and DNA elements in the control regions of genes.

Regulatory mechanisms governing transcription involve several broad areas. The first of these involves the “global” structure of the transcribed substrate, the chromosomal DNA. In living cells, the chromosomal DNA forms a densely packed structure called chromatin, a DNA-histone protein complex. When transcription starts, transcription regulators and co-regulators change the structure of chromatin so that the transcription machinery can access the specific DNA sites for transcriptional initiation. A second important component in the regulation of gene expression is the DNA sequence of the core promoter. The core promoter is the minimum essential DNA region for accurate transcription to occur and contains the recognition site for the basal transcription machinery to start transcription. Since different core promoters show different responses to regulatory signals, it is important to characterize properties of individual core promoters in order to understand transcriptional regulation. The properties of each core promoter are determined by the DNA elements called core promoter elements present in the core promoter. There are several core promoter elements identified to date, which include the TATA box, the Initiator (Inr), and the down stream promoter element (DPE). However, recent analyses of the human genome and its transcripts have revealed that there are a large number of genes that do not contain any of the known core promoter elements. Consequently, my laboratory is focusing on elucidating the mechanisms of transcriptional initiation from this large class of promoters that do not contain previously characterized core promoter elements.

We have recently identified a new core promoter element XCPE1 (X core promoter element 1) in the analysis of the hepatitis B virus X gene promoter. Subsequently, we found that XCPE1 is also found in many TATA-less promoters of human genes. We are currently determining what set of general transcription factors and cofactors are required for transcription from this category of TATA-less promoters. We are going to examine what interactions among the required factors and the core promoter DNAs are utilized for RNA polymerase II recruitment to these promoters. We are also interested in how the core promoter factors and chromatin regulators co-operate with each other to accomplish properly regulated transcription.

Recent publications

Wang X, Truckses DM, Takada S, Matsumura T, Tanese N, Jacobson RH. (2007) Conserved region I of human coactivator TAF4 binds to a short hydrophobic motif present in transcriptional regulators. Proc. Natl. Acad. Sci. USA 104:7839–7844.
Tokusumi Y, Ma Y, Song X, Jacobson, RH, Takada S. (2007) A new core promoter element XCPE1 (X core promoter element 1) directs activator-, mediator-, and TBP-dependent but TFIID-independent RNA polymerase II transcription from TATA-less promoters. Molecular and Cellular Biology 27:1844–1858.
Isogai Y, Takada S, Tjian R, Keles S. (2007) Novel TRF1/BRF target gene revealed by genome-wide analysis of Drosophila Pol III transcription. EMBO Journal 26:78–89.
Bhattacharya S, Takada S, Jacobson RH. (2007) Structural Analysis and Dimerization potential of the human TAF5 subunit of TFIID. Proc. Natl. Acad. Sci. USA 104:1189–1194.
Tokusumi, Y, Zhou S and Takada S (2004) Nuclear respiratory factor 1 (NRF1) plays an essential role in transcriptional initiation form the hepatitis B viral X gene promoter. J. Virol. 78:10856–10864.
Takada S, Lis JT, Zhou S, Tjian R (2000) A TRF1:BRF complex directs Drosophila RNA polymerase III transcription. Cell 101:459–469.
Takada S, Shirakata Y, Kaneniwa N, Koike K (1999) Association of hepatitis B virus X protein with mitochondria causes mitochondrial aggregation at the nuclear periphery, leading to cell death. Oncogene 18:6965–6973.
Hansen SK, Takada S, Jacobson RH, Lis JT, Tjian R (1997) Transcription properties of a cell type-specific TATA-binding protein, TRF. Cell 91:71–83.
Takada S, Kaneniwa N, Tsuchida N, Koike K (1997) Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells. Oncogene 15:1895–1901.
Takada S, Kaneniwa N, Tsuchida N, Koike K (1996) Hepatitis B virus X gene expression is activated by X protein but repressed by p53 tumor suppressor gene product in the transient expression system. Virology 216:80–89.