Table of Contents

Volume 3, Issue 2

  March/April 2012

  Pages 45 - 104

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EDITOR'S PREVIEW

Open Access Article

In this issue of Transcription

Barbara P. Rattner
Page 45
http://dx.doi.org/10.4161/trns.19826
PDF




COMMENTARIES

Open Access Article

The binding site and mechanism of the RNA polymerase inhibitor tagetitoxin: An issue open to debate

Sergiy Klyuyev and Dmitry G. Vassylyev
Pages 46 - 50
http://dx.doi.org/10.4161/trns.19468
Abstract | PDF

In a recent paper in the Journal of Biological Chemistry, Artsimovitch et al.² report a major revision of a crystallographic model and proposed mechanism of the RNA polymerase inhibitor, tagetitoxin. This reassessment is based on theoretical modeling using molecular dynamics simulations. Here, we argue that this theoretical model contradicts experimental results and a published crystal structure cannot exclude several mechanistically distinct alternative models and does not support some major conclusions. We conclude that understanding the tagetitoxin mechanism is beyond the reach of currently available computational simulations and must await input from high-resolution crystal structures of tagetitoxin bound to elongation complex, extensive biochemical studies, or both.

Open Access Article

Response to Klyuyev and Vassylyev: On the mechanism of tagetitoxin inhibition of transcription

Vladimir Svetlov, Irina Artsimovitch and Evgeny Nudler
Pages 51 - 55
http://dx.doi.org/10.4161/trns.19749
Abstract | PDF

In their commentary, Klyuyev and Vassylyev dispute a model of transcription inhibition by tagetitoxin (Tgt) proposed by us based on biochemical analysis and computational docking. We maintain that, although an alternative explanation can be provided for any single observation reported by us, taken together our results support a model in which Tgt acts by trapping the trigger loop (TL) in an inactive state (Artsimovitch et al.).¹ This model is consistent with all the data collected with a physiological target for the inhibitor, the transcription elongation complex (EC). The Tgt-binding pose in our model is indeed different from that observed in the structure of the Thermus thermophilus RNA polymerase (RNAP) holoenzyme in the absence of nucleic acids (Vassylyev et al. Nat Struct Mol Biol 2005; 12:1086). The latter can hardly be considered a dogma because (1) RNAP undergoes conformational changes in the course of the transcription cycle and during catalysis and (2) small molecules containing phosphates likely bind to several sites on RNAP, with the crystallographic site/pose not necessarily being the one most relevant mechanistically. Furthermore, the model proposed based on the Tgt/holoenzyme structure does not explain the inhibitor’s effects on transcript elongation and RNAP translocation. These arguments necessitate further inquiry into the mechanism of inhibition by Tgt by techniques orthogonal to X-ray crystallography. In our opinion, elucidation of a molecular mechanism of any RNAP inhibitor and the follow-up design of more potent derivatives requires a combination of approaches, including genetics, biochemistry, biophysics, X-ray crystallography and computational analysis.




POINTS-OF-VIEW

Open Access Article

Mapping gene-environment interactions at regulatory polymorphisms: Insights into mechanisms of phenotypic variation

Joseph C. Maranville, Francesca Luca, Matthew Stephens and Anna Di Rienzo
Pages 56 - 62
http://dx.doi.org/10.4161/trns.19497
Abstract | PDF

Genetic effects on gene regulation make a substantial contribution to phenotypic diversity, yet their mechanisms remain elusive. Here, we discuss the potential insights to be gained from mapping gene-environment interactions at regulatory polymorphisms (i.e., genetic variation that affects gene expression under specific environmental conditions). We highlight a novel statistical method to identify specific patterns of gene-environment interaction at these regulatory polymorphisms. Reviewing its application to a study that mapped gene expression in the presence and absence of glucocorticoids, we discuss the mechanistic insights that this approach provides.

Open Access Article

A novel mechanism of bacterial adaptation mediated by copper-dependent RNA polymerase σ factors

José Muñoz-Dorado, Nuria Gómez-Santos and Juana Pérez
Pages 63 - 67
http://dx.doi.org/10.4161/trns.19498
Abstract | PDF

One of the mechanisms widely used by bacteria to adapt to their environment is mediated by alternative σ factors. Here we discuss the mechanism of action of a novel metal-dependent ECF σ factor, whose ability to bind DNA depends on the redox state of copper.

Open Access Article

Transcriptional control of Gad2

Zhizhong Z. Pan
Pages 68 - 72
http://dx.doi.org/10.4161/trns.19511
Abstract | PDF

Gad2 encodes GAD65, which is present preferentially in presynaptic terminals for synthesis of GABA for vesicle release. Gad2 is a regulatory target of cell activities in various brain functions and in GABA perturbation-related neurological diseases. However, our understanding of how Gad2 is transcriptionally regulated and how Gad2 transcription responds to changing cell environment under these conditions is still limited. This review discusses recent advances in the regulatory mechanisms for Gad2 transcription and highlights the characteristics of TATA-less Gad2 promoters and regulation of Gad2 transcription by CREB and by activity-dependent epigenetic modification of the chromatin structure in regulatory elements of the Gad2 gene.

Open Access Article

CTCF-dependent chromatin insulator as a built-in attenuator of angiogenesis

Jianrong Lu and Ming Tang
Pages 73 - 77
http://dx.doi.org/10.4161/trns.19634
Abstract | PDF

VEGF is a pivotal pro-angiogenic growth factor and its dosage decisively impacts vascularization. We recently identified a CTCF-dependent chromatin insulator that critically restrains the transcriptional induction of VEGF and angiogenesis. We postulate that CTCF may exert enhancer blocking by mediating chromatin looping and/or RNA polymerase pausing at the VEGF locus.

Open Access Article

Transcription control by long non-coding RNAs

Tyler Faust, Alan Frankel and Iván D'Orso
Pages 78 - 86
http://dx.doi.org/10.4161/trns.19349
Abstract | PDF

Non-coding RNAs have been found to regulate many cellular processes and thus expand the functional genetic repertoire contained within the genome. With the recent advent of genomic tools, it is now evident that these RNA molecules play central regulatory roles in many transcriptional programs. Here we discuss how they are targeted to promoters in several cases and how they operate at specific points in the transcription cycle to precisely control gene expression.




REVIEW

Open Access Article

Synthetic in vitro transcription circuits

Maximilian Weitz and Friedrich C. Simmel
Pages 87 - 91
http://dx.doi.org/10.4161/trns.19734
Abstract | PDF

With the help of only two enzymes—an RNA polymerase and a ribonuclease—reduced versions of transcriptional regulatory circuits can be implemented in vitro. These circuits enable the emulation of naturally occurring biochemical networks, the exploration of biological circuit design principles and the biochemical implementation of powerful computational models.




RESEARCH PAPER

Open Access Article

A novel TBP-TAF complex on RNA Polymerase II-transcribed snRNA genes

Justyna Zaborowska, Alice Taylor, Robert G. Roeder and Shona Murphy
Pages 92 - 104
http://dx.doi.org/10.4161/trns.19783
Abstract | PDF

Initiation of transcription of most human genes transcribed by RNA polymerase II (RNAP II) requires the formation of a preinitiation complex comprising TFIIA, B, D, E, F, H and RNAP II. The general transcription factor TFIID is composed of the TATA-binding protein and up to 13 TBP-associated factors. During transcription of snRNA genes, RNAP II does not appear to make the transition to long-range productive elongation, as happens during transcription of protein-coding genes. In addition, recognition of the snRNA gene-type specific 3′ box RNA processing element requires initiation from an snRNA gene promoter. These characteristics may, at least in part, be driven by factors recruited to the promoter. For example, differences in the complement of TAFs might result in differential recruitment of elongation and RNA processing factors. As precedent, it already has been shown that the promoters of some protein-coding genes do not recruit all the TAFs found in TFIID. Although TAF5 has been shown to be associated with RNAP II-transcribed snRNA genes, the full complement of TAFs associated with these genes has remained unclear. Here we show, using a ChIP and siRNA-mediated approach, that the TBP/TAF complex on snRNA genes differs from that found on protein-coding genes. Interestingly, the largest TAF, TAF1, and the core TAFs, TAF10 and TAF4, are not detected on snRNA genes. We propose that this snRNA gene-specific TAF subset plays a key role in gene type-specific control of expression.