Diana Ideses

Bio: Diana Ideses is an academic researcher from Bar-Ilan University. The author has contributed to research in topics: Promoter & General transcription factor. The author has an hindex of 6, co-authored 12 publications receiving 247 citations.

Drosophila TRF2 is a preferential core promoter regulator.

Abstract: Transcription of protein-coding genes is highly dependent on the RNA polymerase II (Pol II) core promoter. Core promoters, generally defined as the regions that direct transcription initiation, span from −40 to +40 relative to the +1 transcription start site (TSS). Core promoters contain functional subregions (termed core promoter elements or motifs, such as the TATA-box, TFIIB recognition elements [BREu and BREd], initiator [Inr], TCT motif, motif 10 element [MTE], and downstream core promoter element [DPE]) that confer specific properties to the core promoter (for review, see Smale 2001; Smale and Kadonaga 2003; Thomas and Chiang 2006; Deng and Roberts 2007; Heintzman and Ren 2007; Juven-Gershon et al. 2008b; Juven-Gershon and Kadonaga 2010; Kadonaga 2012; Lenhard et al. 2012). A synthetic core promoter (termed the super core promoter [SCP]) that contains a TATA, Inr, MTE, and DPE in a single promoter has been shown to yield high levels of transcription, implying that gene expression levels can be modulated via the core promoter (Juven-Gershon et al. 2006). The set of basal transcription factors has been defined using TATA-dependent promoters (for review, see Thomas and Chiang 2006). Transcription of DPE-dependent genes, however, is fundamentally different from transcription of TATA-dependent genes. First and foremost, the set of basal transcription factors that is necessary to transcribe TATA-dependent promoters in vitro is insufficient to transcribe DPE-dependent promoters (Lewis et al. 2005; Goodrich and Tjian 2010). Moreover, enhancers with a preference for DPE-containing promoters or TATA-containing promoters have been discovered (Ohtsuki et al. 1998; Butler and Kadonaga 2001, 2002; Smale 2001). Furthermore, TBP, which is necessary for TATA-dependent transcription, down-regulates DPE-dependent transcription (Hsu et al. 2008). Additionally, NC2 and MOT1, which are positive regulators of DPE-dependent transcription, act by counteracting TBP, thus relieving its inhibition of DPE transcription (Willy et al. 2000; Hsu et al. 2008; van Werven et al. 2008). DPE-dependent promoters can be transcribed using Drosophila high-salt nuclear extracts (Willy et al. 2000). To identify the factors that support DPE-dependent transcription, we used a biochemical complementation approach and fractionated high-salt nuclear extracts in search of proteins that would support DPE transcription. We discovered that TBP (TATA-box-binding protein)-related factor 2 (TRF2) is enriched in the fractions supporting DPE transcription. Drosophila trf2 encodes two protein isoforms that show similarity to the core domain of TBP: a 632-amino-acid protein (the “short TRF2,” which has been extensively studied) and a 1715-amino-acid protein in which the same short TRF2 sequence is preceded by a long N-terminal domain (Kopytova et al. 2006). We explored the functions of TRF2, which is the TRF with the least similarity to TBP, in transcriptional regulation and discovered that short TRF2 preferentially binds and activates DPE-containing promoters. This study highlights the role of short TRF2 as a preferential core promoter regulator and provides insights into the complexity of transcription initiation.

A novel mitosis-associated lncRNA, MA-linc1, is required for cell cycle progression and sensitizes cancer cells to Paclitaxel

Abstract: Long noncoding RNAs (lncRNAs) are major regulators of many cellular processes including cell cycle progression and tumorigenesis. In this study, we identify a novel lncRNA, MA-linc1, and reveal its effects on cell cycle progression and cancer growth. Inhibition of MA-linc1 expression alters cell cycle distribution, leading to a decrease in the number of G1 cells and a concomitant increase in all other stages of the cell cycle, and in particular G2/M, suggesting its involvement in the regulation of M phase. Accordingly, knock down of MA-linc1 inhibits M phase exit upon release from a mitotic block. We further demonstrate that MA-linc1 predominantly functions in cis to repress expression of its neighboring gene, Purα, which is often deleted in human cancers and whose ectopic expression inhibits cell cycle progression. Knock down of Purα partially rescues the MA-linc1 dependent inhibition of M phase exit. In agreement with its suggested role in M phase, inhibition of MA-linc1 enhances apoptotic cell death induced by the antimitotic drug, Paclitaxel and this enhancement of apoptosis is rescued by Purα knockdown. Furthermore, high levels of MA-linc1 are associated with reduced survival in human breast and lung cancer patients.Taken together, our data identify MA-linc1 as a novel lncRNA regulator of cell cycle and demonstrate its potential role in cancer progression and treatment.

Engineered Promoters for Potent Transient Overexpression.

Abstract: The core promoter, which is generally defined as the region to which RNA Polymerase II is recruited to initiate transcription, plays a pivotal role in the regulation of gene expression. The core promoter consists of different combinations of several short DNA sequences, termed core promoter elements or motifs, which confer specific functional properties to each promoter. Earlier studies that examined the ability to modulate gene expression levels via the core promoter, led to the design of strong synthetic core promoters, which combine different core elements into a single core promoter. Here, we designed a new core promoter, termed super core promoter 3 (SCP3), which combines four core promoter elements (the TATA box, Inr, MTE and DPE) into a single promoter that drives prolonged and potent gene expression. We analyzed the effect of core promoter architecture on the temporal dynamics of reporter gene expression by engineering EGFP expression vectors that are driven by distinct core promoters. We used live cell imaging and flow cytometric analyses in different human cell lines to demonstrate that SCPs, particularly the novel SCP3, drive unusually strong long-term EGFP expression. Importantly, this is the first demonstration of long-term expression in transiently transfected mammalian cells, indicating that engineered core promoters can provide a novel non-viral strategy for biotechnological as well as gene-therapy-related applications that require potent expression for extended time periods.

TRF2: TRansForming the view of general transcription factors.

Abstract: Transcriptional regulation is pivotal for development and differentiation of organisms. Transcription of eukaryotic protein-coding genes by RNA polymerase II (Pol II) initiates at the core promoter. Core promoters, which encompass the transcription start site, may contain functional core promoter elements, such as the TATA box, initiator, TCT and downstream core promoter element. TRF2 (TATA-box-binding protein-related factor 2) does not bind TATA box-containing promoters. Rather, it is recruited to core promoters via sequences other than the TATA box. We review the recent findings implicating TRF2 as a basal transcription factor in the regulation of diverse biological processes and specialized transcriptional programs.

A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response

Abstract: Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.

Eukaryotic core promoters and the functional basis of transcription initiation

Abstract: RNA polymerase II (Pol II) core promoters are specialized DNA sequences at transcription start sites of protein-coding and non-coding genes that support the assembly of the transcription machinery and transcription initiation. They enable the highly regulated transcription of genes by selectively integrating regulatory cues from distal enhancers and their associated regulatory proteins. In this Review, we discuss the defining properties of gene core promoters, including their sequence features, chromatin architecture and transcription initiation patterns. We provide an overview of molecular mechanisms underlying the function and regulation of core promoters and their emerging functional diversity, which defines distinct transcription programmes. On the basis of the established properties of gene core promoters, we discuss transcription start sites within enhancers and integrate recent results obtained from dedicated functional assays to propose a functional model of transcription initiation. This model can explain the nature and function of transcription initiation at gene starts and at enhancers and can explain the different roles of core promoters, of Pol II and its associated factors and of the activating cues provided by enhancers and the transcription factors and cofactors they recruit.

Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases.

Abstract: The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review.