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Functionally distinct promoter classes initiate transcription via different mechanisms reflected in focused versus dispersed initiation patterns

ABSTRACT: Recruitment of RNA polymerase II (Pol II) to promoters is essential for transcription. Despite conflicting evidence, the Pol II Pre-Initiation Complex (PIC) is often thought to have a uniform composition and to assemble at all promoters via an identical mechanism. Here, using Drosophila melanogaster S2 cells as a model, we demonstrate that different promoter classes function via distinct PICs. Promoter DNA of developmentally-regulated genes readily associates with the canonical Pol II PIC, whereas housekeeping promoters do not, and instead recruit other factors such as DREF. Consistently, TBP and DREF are differentially required by distinct promoter types. TBP and its paralog TRF2 also function at different promoter types in a partially redundant manner. In contrast, TFIIA is required at all promoters, and we identify factors that can recruit and/or stabilize TFIIA at housekeeping promoters and activate transcription. Promoter activation by these factors is sufficient to induce the dispersed transcription initiation patterns characteristic of housekeeping promoters. Thus, different promoter classes utilize distinct mechanisms of transcription initiation, which translate into different focused versus dispersed initiation patterns.

SUBMITTER: Dr. Leonid Serebreni

PROVIDER: S-SCDT-10_15252-EMBJ_2023113519 | biostudies-other |

REPOSITORIES: biostudies-other

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Functionally distinct promoter classes initiate transcription via different mechanisms reflected in focused versus dispersed initiation patterns.

Project description:Recruitment of RNA polymerase II (Pol II) to promoters is essential for transcription. Despite conflicting evidence, the Pol II preinitiation complex (PIC) is often thought to have a uniform composition and to assemble at all promoters via an identical mechanism. Here, using Drosophila melanogaster S2 cells as a model, we demonstrate that different promoter classes function via distinct PICs. Promoter DNA of developmentally regulated genes readily associates with the canonical Pol II PIC, whereas housekeeping promoters do not, and instead recruit other factors such as DREF. Consistently, TBP and DREF are differentially required by distinct promoter types. TBP and its paralog TRF2 also function at different promoter types in a partially redundant manner. In contrast, TFIIA is required at all promoters, and we identify factors that can recruit and/or stabilize TFIIA at housekeeping promoters and activate transcription. Promoter activation by tethering these factors is sufficient to induce the dispersed transcription initiation patterns characteristic of housekeeping promoters. Thus, different promoter classes utilize distinct mechanisms of transcription initiation, which translate into different focused versus dispersed initiation patterns.

| S-EPMC10183819 | biostudies-literature

Functionally distinct promoter classes initiate transcription via different mechanisms [PRO-Seq]

Project description:To identify the functional contribution to transcription of various promoter-bound proteins we have endogenously tagged select proteins with an auxin-inducible degron and measured nascent transcription with PRO-seq 6 hours after their depletion

2023-03-02 | GSE181257 | GEO

Functionally distinct promoter classes initiate transcription via different mechanisms [PRO-Seq]

Project description:Functionally distinct promoter classes initiate transcription via different mechanisms [PRO-Seq]

| PRJNA751383 | ENA

Linking Core Promoter Classes to Circadian Transcription.

Project description:Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin states of genes transcribed in a circadian manner in mouse liver and in Drosophila. It is shown that the core promoter is a critical determinant of circadian mRNA expression in both species. A distinct core promoter class, strong circadian promoters (SCPs), is identified in mouse liver but not Drosophila. SCPs are defined by specific core promoter features, and are shown to drive circadian transcriptional activities with both high averages and high amplitudes. Data analysis and mathematical modeling further provided evidence for rhythmic regulation of both polymerase II recruitment and pause release at SCPs. The analysis provides a comprehensive and systematic view of core promoters and their link to circadian mRNA expression in mouse and Drosophila, and thus reveals a crucial role for the core promoter in regulated, dynamic transcription.

| S-EPMC4978467 | biostudies-literature

Three functionally distinct classes of C-fibre nociceptors in primates.

Project description:In primates, C-fibre polymodal nociceptors are broadly classified into two groups based on mechanosensitivity. Here we demonstrate that mechanically sensitive polymodal nociceptors that respond either quickly (QC) or slowly (SC) to a heat stimulus differ in responses to a mild burn, heat sensitization, conductive properties and chemosensitivity. Superficially applied capsaicin and intradermal injection of β-alanine, an MrgprD agonist, excite vigorously all QCs. Only 40% of SCs respond to β-alanine, and their response is only half that of QCs. Mechanically insensitive C-fibres (C-MIAs) are β-alanine insensitive but vigorously respond to capsaicin and histamine with distinct discharge patterns. Calcium imaging reveals that β-alanine and histamine activate distinct populations of capsaicin-responsive neurons in primate dorsal root ganglion. We suggest that histamine itch and capsaicin pain are peripherally encoded in C-MIAs, and that primate polymodal nociceptive afferents form three functionally distinct subpopulations with β-alanine responsive QC fibres likely corresponding to murine MrgprD-expressing, non-peptidergic nociceptive afferents.

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Predicting functionally important SNP classes based on negative selection.

Project description:With the advent of cost-effective genotyping technologies, genome-wide association studies allow researchers to examine hundreds of thousands of single nucleotide polymorphisms (SNPs) for association with human disease. Recently, many researchers applying this strategy have detected strong associations to disease with SNP markers that are either not in linkage disequilibrium with any nonsynonymous SNP or large distances from any annotated gene. In such cases, no well-established standard practice for effective SNP selection for follow-up studies exists. We aim to identify and prioritize groups of SNPs that are more likely to affect phenotypes in order to facilitate efficient SNP selection for follow-up studies.Based on the annotations available in the Ensembl database, we categorized SNPs in the human genome into classes related to regulatory attributes, such as epigenetic modifications and transcription factor binding sites, in addition to classes related to gene structure and cross-species conservation. Using the distribution of derived allele frequencies (DAF) within each class, we assessed the strength of natural selection for each class relative to the genome as a whole. We applied this DAF analysis to Perlegen resequenced SNPs genome-wide. Regulatory elements annotated by Ensembl such as specific histone methylation sites as well as classes defined by cross-species conservation showed negative selection in comparison to the genome as a whole.These results highlight which annotated classes are under purifying selection, have putative functional importance, and contain SNPs that are strong candidates for follow-up studies after genome-wide association. Such SNP annotation may also be useful in interpreting results of whole-genome sequencing studies.

| S-EPMC3033802 | biostudies-other

Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.

Project description:Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavourable prognostic sign in certain advanced prostate tumours, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA) based on global nuclear run-on sequencing (GRO-seq) analysis, with a unique class apparently requiring no nucleosome remodelling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.

| S-EPMC3117022 | biostudies-literature

Analysis of regulatory network topology reveals functionally distinct classes of microRNAs.

Project description:MicroRNAs (miRNAs) negatively regulate the expression of target genes at the post-transcriptional level. Little is known about the crosstalk between miRNAs and transcription factors (TFs). Here we provide data suggesting that the interaction patterns between TFs and miRNAs can influence the biological functions of miRNAs. From this global survey, we find that a regulated feedback loop, in which two TFs regulate each other and one miRNA regulates both of the factors, is the most significantly overrepresented network motif. Mathematical modeling shows that the miRNA in this motif stabilizes the feedback loop to resist environmental perturbation, providing one mechanism to explain the robustness of developmental programs that is contributed by miRNAs. Furthermore, on the basis of a network motif profile analysis, we demonstrate the existence of two classes of miRNAs with distinct network topological properties. The first class of miRNAs is regulated by a large number of TFs, whereas the second is regulated by only a few TFs. The differential expression level of the two classes of miRNAs in embryonic developmental stages versus adult tissues suggests that the two classes may have fundamentally different biological functions. Our results demonstrate that the TFs and miRNAs extensively interact with each other and the biological functions of miRNAs may be wired in the regulatory network topology.

| S-EPMC2582613 | biostudies-literature

Bioequivalence of dispersed stavudine: opened versus closed capsule dosing.

Project description:Stavudine, a nucleoside reverse transcriptase inhibitor, is used commonly to treat HIV-infected children in the developing world. The paediatric liquid formulation presents major logistical difficulties in rural and resource-limited areas, and prescribers are frequently forced to employ off-label 'opened capsule' dosing methods using the adult capsule. The South African Department of Health (DoH) has advised that caregivers should be instructed to disperse the contents of an adult capsule in 5 ml water and then withdraw the required dose using a syringe. The bioavailability of stavudine using the opened capsule dosing method has not previously been validated.This was a randomized crossover pharmacokinetic study with each subject serving as his/her own control. A total of 28 healthy HIV-negative adult volunteers were randomized on a 1:1 basis to receive one of the two generic preparations typically available in state hospitals. They were then further randomized to receive either intact or opened 30 mg capsules. After 1 week, those who initially received intact capsules, were given opened capsules and vice versa. The capsule dispersion technique used was identical to that prescribed by the DoH. Serial blood samples were collected and plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Stavudine pharmacokinetics were analysed using non-compartmental methods and formulations were compared using ANOVA.Plasma drug exposure after stavudine administration as a solution using an opened capsule dosing method was found to be bioequivalent to intact capsule administration. This was true for both generics tested.The opened capsule dosing technique is bioequivalent to intact capsule dosing for stavudine in HIV-seronegative adults.

| S-EPMC5054241 | biostudies-literature

Versatile strategy for homogeneous drying patterns of dispersed particles.

Project description:After spilling coffee, a tell-tale stain is left by the drying droplet. This universal phenomenon, known as the coffee ring effect, is observed independent of the dispersed material. However, for many technological processes such as coating techniques and ink-jet printing a uniform particle deposition is required and the coffee ring effect is a major drawback. Here, we present a simple and versatile strategy to achieve homogeneous drying patterns using surface-modified particle dispersions. High-molecular weight surface-active polymers that physisorb onto the particle surfaces provide enhanced steric stabilization and prevent accumulation and pinning at the droplet edge. In addition, in the absence of free polymer in the dispersion, the surface modification strongly enhances the particle adsorption to the air/liquid interface, where they experience a thermal Marangoni backflow towards the apex of the drop, leading to uniform particle deposition after drying. The method is independent of particle shape and applicable to a variety of commercial pigment particles and different dispersion media, demonstrating the practicality of this work for everyday processes.

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