Transcription-Austin最新文献

RNA polymerases are the central enzymes of gene expression and function frequently in either a head-on or co-directional manner on the busy DNA track. Whether and how these collisions between RNA polymerases contribute to transcriptional regulation is mysterious. Increasing evidence from biochemical and single-molecule studies suggests that RNA polymerase collisions function as an important regulator to fine-tune transcription, rather than creating deleterious "traffic jams". This review summarizes the recent progress on elucidating the consequences of RNA polymerase collisions during transcription and highlights the significance of cooperation and coordination between RNA polymerases.

The preservation of gene expression patterns that define cellular identity throughout the cell division cycle is essential to perpetuate cellular lineages. However, the progression of cells through different phases of the cell cycle severely disrupts chromatin accessibility, epigenetic marks, and the recruitment of transcriptional regulators. Notably, chromatin is transiently disassembled during S-phase and undergoes drastic condensation during mitosis, which is a significant challenge to the preservation of gene expression patterns between cell generations. This article delves into the specific gene expression and chromatin regulatory mechanisms that facilitate the preservation of transcriptional identity during replication and mitosis. Furthermore, we emphasize our recent findings revealing the unconventional role of yeast centromeres and mitotic chromosomes in maintaining transcriptional fidelity beyond mitosis.

DNA replication and RNA transcription both utilize DNA as a template and therefore need to coordinate their activities. The predominant theory in the field is that in order for the replication fork to proceed, transcription machinery has to be evicted from DNA until replication is complete. If that does not occur, these machineries collide, and these collisions elicit various repair mechanisms which require displacement of one of the enzymes, often RNA polymerase, in order for replication to proceed. This model is also at the heart of the epigenetic bookmarking theory, which implies that displacement of RNA polymerase during replication requires gradual re-building of chromatin structure, which guides recruitment of transcriptional proteins and resumption of transcription. We discuss these theories but also bring to light newer data that suggest that these two processes may not be as detrimental to one another as previously thought. This includes findings suggesting that these processes can occur without fork collapse and that RNA polymerase may only be transiently displaced during DNA replication. We discuss potential mechanisms by which RNA polymerase may be retained at the replication fork and quickly rebind to DNA post-replication. These discoveries are important, not only as new evidence as to how these two processes are able to occur harmoniously but also because they have implications on how transcriptional programs are maintained through DNA replication. To this end, we also discuss the coordination of replication and transcription in light of revising the current epigenetic bookmarking theory of how the active gene status can be transmitted through S phase.

The rising threat of antibiotic resistance in pathogenic bacteria emphasizes the need for new therapeutic strategies. This review focuses on bacterial transcription factors (TFs), which play crucial roles in bacterial pathogenesis. We discuss the regulatory roles of these factors through examples, and we outline potential therapeutic strategies targeting bacterial TFs. Specifically, we discuss the use of small molecules to interfere with TF function and the development of transcription factor decoys, oligonucleotides that compete with promoters for TF binding. We also cover peptides that target the interaction between the bacterial TF and other factors, such as RNA polymerase, and the targeting of sigma factors. These strategies, while promising, come with challenges, from identifying targets to designing interventions, managing side effects, and accounting for changing bacterial resistance patterns. We also delve into how Artificial Intelligence contributes to these efforts and how it may be exploited in the future, and we touch on the roles of multidisciplinary collaboration and policy to advance this research domain.Abbreviations: AI, artificial intelligence; CNN, convolutional neural networks; DTI: drug-target interaction; HTH, helix-turn-helix; IHF, integration host factor; LTTRs, LysR-type transcriptional regulators; MarR, multiple antibiotic resistance regulator; MRSA, methicillin resistant Staphylococcus aureus; MSA: multiple sequence alignment; NAP, nucleoid-associated protein; PROTACs, proteolysis targeting chimeras; RNAP, RNA polymerase; TF, transcription factor; TFD, transcription factor decoying; TFTRs, TetR-family transcriptional regulators; wHTH, winged helix-turn-helix.

Immune function is highly controlled at the transcriptional level by the binding of transcription factors (TFs) to promoter and enhancer elements. Several TF families play major roles in immune gene expression, including NF-κB, STAT, IRF, AP-1, NRs, and NFAT, which trigger anti-pathogen responses, promote cell differentiation, and maintain immune system homeostasis. Aberrant expression, activation, or sequence of isoforms and variants of these TFs can result in autoimmune and inflammatory diseases as well as hematological and solid tumor cancers. For this reason, TFs have become attractive drug targets, even though most were previously deemed "undruggable" due to their lack of small molecule binding pockets and the presence of intrinsically disordered regions. However, several aspects of TF structure and function can be targeted for therapeutic intervention, such as ligand-binding domains, protein-protein interactions between TFs and with cofactors, TF-DNA binding, TF stability, upstream signaling pathways, and TF expression. In this review, we provide an overview of each of the important TF families, how they function in immunity, and some related diseases they are involved in. Additionally, we discuss the ways of targeting TFs with drugs along with recent research developments in these areas and their clinical applications, followed by the advantages and disadvantages of targeting TFs for the treatment of immune disorders.

Caenorhabditis elegans can enter a diapause stage called "dauer" when it senses that the environment is not suitable for development. This implies a detour from the typical developmental trajectory and requires a tight control of the developmental clock and a massive tissue remodeling. In the last decades, core components of the signaling pathways that govern the dauer development decision have been identified, but the tissues where they function for the acquisition of dauer-specific traits are still under intense study. Growing evidence demonstrates that these pathways engage in complex cross-talk and feedback loops. In this review, we summarize the current knowledge regarding the transcriptional regulation of the dauer program and the relevant tissues for its achievement. A better understanding of this process will provide insight on how developmental plasticity is achieved and how development decisions are under a robust regulation to ensure an all-or-nothing response. Furthermore, this developmental decision can also serve as a simplified model for relevant developmental disorders.Abbreviations: AID Auxin Induced Degron DA dafachronic acid Daf-c dauer formation constitutive Daf-d dauer formation defective DTC Distal Tip Cells ECM modified extracellular matrix GPCRs G protein-coupled receptors IIS insulin/IGF-1 signaling ILPs insulin-like peptides LBD Ligand Binding Domain PDL4 Post Dauer L4 TGF-β transforming growth factor beta WT wild-type.

Eukaryotic cells rely upon dynamic, multifaceted regulation at each step of RNA biogenesis to maintain mRNA pools and ensure normal protein synthesis. Studies in budding yeast indicate a buffering phenomenon that preserves global mRNA levels through the reciprocal balancing of RNA synthesis rates and mRNA decay. In short, changes in transcription impact the efficiency of mRNA degradation and defects in either nuclear or cytoplasmic mRNA degradation are somehow sensed and relayed to control a compensatory change in mRNA transcription rates. Here, we review current views on molecular mechanisms that might explain this apparent bidirectional sensing process that ensures homeostasis of the stable mRNA pool.

RNA polymerase II (Pol II) is composed of 12 subunits that collaborate to synthesize mRNA within the nucleus. Pol II is widely recognized as a passive holoenzyme, with the molecular functions of its subunits largely ignored. Recent studies employing auxin-inducible degron (AID) and multi-omics techniques have revealed that the functional diversity of Pol II is achieved through the differential contributions of its subunits to various transcriptional and post-transcriptional processes. By regulating these processes in a coordinated manner through its subunits, Pol II can optimize its activity for diverse biological functions. Here, we review recent progress in understanding Pol II subunits and their dysregulation in diseases, Pol II heterogeneity, Pol II clusters and the regulatory roles of RNA polymerases.

Microsporidia are eukaryotic obligate intracellular parasites closely related to fungi. Co-evolving with infected hosts, microsporidia have highly reduced their genomes and lacked several biological components. As it is beneficial for intracellular parasites like microsporidia to reduce their genome size, it is therefore reasonable to assume that genes encoding multifactorial complex machinery of transcription could be a potential target to be excluded from microsporidian genomes during the reductive evolution. In such a case, an evolutionary dilemma occurs because microsporidia cannot remove all transcription-machinery-encoding genes, products of which are essential for initialthe initial steps of gene expression. Here, I propose that while genes encoding core machinery are conserved, several genes known to function in fine-tune regulation of transcription are absent. This genome compaction strategy may come at the cost of loosely regulated or less controllable transcription. Alternatively, analogous to microsporidian polar tube, the parasites may have specialized factors to regulate their RNA synthesis.