Biology subjects

Tripathi, S.

Publications and source records attributed to Tripathi, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Human antigen R differentially modulates the translation of SARS-CoV-2 genomic and sub-genomic RNAs

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) viral RNA associates with different RNA-binding host proteins at each stage of its life cycle. We found sequence dependent binding of one such important protein, human antigen R (HuR) to SARS-CoV-2 5'UTR and studied its potential role in virus life cycle. The knockdown and knockout studies revealed importance of such binding in viral translation. We identified 5'-UTR mutations in SARS-CoV-2 variants of concern that altered the HuR-binding affinity. Interestingly, HuR enhanced non-structural protein translation through the genomic 5'-UTR, by promoting polypyrimidine tract-binding protein binding to the 5'-UTR. However, HuR suppressed the structural protein translation from sub genomic 5UTR. HuR knockout increased the sensitivity to remdesivir treatment by decreasing its half-maximal inhibitory concentration. An antisense oligonucleotide (whose binding site overlapped the HuR-binding site) reduced viral RNA levels in wild-type cells but not HuR-knockout cells. Our results indicate that HuR regulates the balance between SARS-CoV-2 structural and non-structural proteins and guides the infection of viral variants, implying that HuR can potentially be targeted for therapeutic interventions. Author SummaryViruses interacts with various host proteins throughout their life cycle. One significant protein is HuR, an RNA-binding protein that regulates RNA stability and translation. HuR binds to viral RNAs at the 5UTR or 3UTR, impacting their translation and replication. We identified conserved HuR binding sites in the SARS-CoV-2 5UTR across different beta coronaviruses. This binding enhanced the initiation of translation from the genomic 5 UTR, increasing the production of non-structural proteins essential for viral replication. Additionally, we discovered that another host protein, PTB, promotes HuR binding to the viral 5 UTR, facilitating its loading onto ribosomes. Conversely, HuR plays an antagonistic role concerning subgenomic RNAs (sgRNAs), which code for structural proteins, by regulating and limiting their levels. This dual regulation indicates that the virus exploits HuR for its benefit while the host employs it to control viral spread. Targeting HuR may help manipulate the SARS-CoV-2 life cycle. We found that HuR knockout increased sensitivity to the antiviral drug Remdesivir. Using an antisense oligonucleotide to block HuR binding effectively reduced viral RNA levels. Our findings highlight the critical role of HuR in regulating viral protein production and its potential as a therapeutic target.

microbiology↗

bioRxiv2023

A prebiotic genetic alphabet as an early Darwinian ancestor for pre-RNA evolution

RNA-based genetic code is thought to be central to lifes emergence due to its dual ability for information transfer and catalysis. Nonetheless, the genetic code of early life was potentially not restricted to canonical genetic alphabets alone. The presence of an extensive repertoire of modified nucleobases in extant biology as signatures of the past, highlights the relevance of non-canonical alphabets, ably strengthened by experiments demonstrating their ready conversion into nucleosides and nucleotides. All these strongly support a pre-RNA World, wherein informational molecules are posited to have contained alternate genetic alphabets. Nevertheless, understanding pre-RNA molecules capacity to acquire emergent function has remained less prevalent. Further, the steps involved in their transition to a canonical RNA World has not been systematically studied in the origins of life framework. In this study, we report the synthesis of a prebiotically relevant genetic alphabet containing the non-canonical nucleobase, barbituric acid. We demonstrate for the first instance the enzymatic incorporation of this prebiotically plausible alphabet (BaTP) into an RNA, using proteinaceous T7 RNA polymerase. Pertinently, the incorporation of this genetic alphabet into a baby spinach aptamer did not affect its overall secondary structure, while also allowing it to retain its aptameric function. Furthermore, we demonstrate the faithful transfer of genetic information from pre-RNA-containing barbitudine nucleotides to DNA, using a high-fidelity RNA-dependent DNA polymerase. These findings allude to a putative pathway for the early molecular evolution of the genetic code of extant life.

biochemistry↗

bioRxiv2023

A method for predicting linear and conformational B-cell epitopes in an antigen from its primary sequence

B-cell is an essential component of the immune system that plays a vital role in providing the immune response against any pathogenic infection by producing antibodies. Existing methods either predict linear or conformational B-cell epitopes in an antigen. In this study, a single method was developed for predicting both types (linear/conformational) of B-cell epitopes. The dataset used in this study contains 3875 B-cell epitopes and 3996 non-B-cell epitopes, where B-cell epitopes consist of both linear and conformational B-cell epitopes. Our primary analysis indicates that certain residues (like Asp, Glu, Lys, Asn) are more prominent in B-cell epitopes. We developed machine-learning based methods using different types of sequence composition and achieved the highest AUC of 0.80 using dipeptide composition. In addition, models were developed on selected features, but no further improvement was observed. Our similarity-based method implemented using BLAST shows a high probability of correct prediction with poor sensitivity. Finally, we came up with a hybrid model that combine alignment free (dipeptide based random forest model) and alignment-based (BLAST based similarity) model. Our hybrid model attained maximum AUC 0.83 with MCC 0.49 on the independent dataset. Our hybrid model performs better than existing methods on an independent dataset used in this study. All models trained and tested on 80% data using cross-validation technique and final model was evaluated on 20% data called independent or validation dataset. A webserver and standalone package named "CLBTope" has been developed for predicting, designing, and scanning B-cell epitopes in an antigen sequence (https://webs.iiitd.edu.in/raghava/clbtope/).

bioinformatics↗

bioRxiv2022

ENHANCED RECOMBINATION AMONG SARS-COV-2 OMICRON VARIANTS CONTRIBUTES TO VIRAL IMMUNE ESCAPE.

SARS-CoV-2 virus evolution occurs as a result of antigenic drift and shift. Although antigenic drift has been extensively studied, antigenic shift, which for SARS-CoV-2 occurs through genetic recombination, has been examined scarcely. To gain a better understanding of the emergence and prevalence of recombinant SARS-CoV-2 lineages through time and space, we analyzed SARS-CoV-2 genome sequences from public databases. Our study revealed an extraordinary increase in the emergence of SARS-CoV-2 recombinant lineages during the Omicron wave, particularly in Northern America and Europe. This phenomenon was independent of sequencing density or genetic diversity of circulating SARS-CoV-2 strains. In SARS-CoV-2 genomes, recombination breakpoints were found to be more concentrated in the 3 UTR followed by ORF1a. Additionally, we noted enrichment of certain amino acids in the spike protein of recombinant lineages, which have been reported to confer immune escape from neutralizing antibodies, increase ACE2 receptor binding, and enhance viral transmission in some cases. Overall, we report an important and timely observation of accelerated recombination in the currently circulating Omicron variants and explore their potential contribution to viral fitness, particularly immune escape.

microbiology↗

bioRxiv2022

PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period

PERIOD (PER) and Casein Kinase 1{delta} regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1{delta} phosphorylation of the Familial Advanced Sleep Phase (FASP) serine cluster embedded within the Casein Kinase 1 binding domain (CK1BD) of mammalian PER1/2 inhibits its activity on phosphodegrons to stabilize PER and extend circadian period. Here, we show that the phosphorylated FASP region (pFASP) of PER2 directly interacts with and inhibits CK1{delta}. Co-crystal structures in conjunction with accelerated molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1{delta}. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortens circadian period in human cells. We found that Drosophila PER also regulates CK1{delta} via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity.

biochemistry↗

bioRxiv2022

Structural basis for tunable affinity and specificity of LxCxEdependentprotein interactions with the retinoblastoma protein family

The retinoblastoma protein (Rb) and its homologs p107 and p130 are critical regulators of gene expression during the cell cycle. Functional inactivation of Rb family proteins leads to loss of cell-cycle control and promotes genome instability and proliferation, which are hallmarks of cancer. Rb proteins share a structural domain, known as the "pocket domain", which mediates association with a large number of cellular proteins. A cleft in the pocket domain binds an LxCxE sequence motif in these proteins, many of which function with Rb proteins to co-regulate transcription during quiescence and G1. Proteins from oncogenic DNA viruses also bind this cleft to inactivate Rb family proteins, and the E7 protein from the human papillomavirus has been used as the primary model for understanding LxCxE motif interactions. Evidence presented previously and here demonstrates that the E7 sequence binds tighter and competes with cellular proteins for the LxCxE site, but the molecular basis for the relatively weak affinities of the cellular proteins has been poorly understood. Here, we present binding data and a series of crystal structures of the p107 pocket domain in complex with LxCxE peptides derived from the transcriptional co-repressor proteins HDAC1, ARI4DA, and EID1. The structures reveal determinants of protein binding beyond the L-C-E core that include the N and C-terminal sides of the LxCxE motif and the x (wild card) residues. Our results explain how differences in these interactions outside the L-C-E core result in weaker affinities of pocket protein for cellular LxCxE proteins compared to E7 and result in differences in Rb and p107 affinities for some LxCxE-containing sequences. Our study provides new insights into how Rb proteins bind their myriad of cell partners and lays the foundation for structure-based design of peptides that inhibit oncogenic viral protein interactions.

biochemistry↗

bioRxiv2022

Minimal frustration underlies the usefulness of incomplete and inexact regulatory network models in biology

Regulatory networks as large and complex as those implicated in cell-fate choice are expected to exhibit intricate, very high-dimensional dynamics. Cell-fate choice, however, is a macroscopically simple process. Additionally, regulatory network models are almost always incomplete and / or inexact, and do not incorporate all the regulators and interactions that may be involved in cellfate regulation. In spite of these issues, regulatory network models have proven to be incredibly effective tools for understanding cell-fate choice across contexts and for making useful predictions. Here, we show that minimal frustration--a feature of biological networks across contexts but not of random networks--can compel simple, low-dimensional steady-state behavior even in large and complex networks. Moreover, the steady-state behavior of minimally frustrated networks can be recapitulated by simpler networks such as those lacking many of the nodes and edges, and those that treat multiple regulators as one. The present study provides a theoretical explanation for the success of network models in biology and for the challenges in network inference.

systems biology↗

bioRxiv2022

Turing Test Inspired Method for Analysis of Biases Prevalent in Artificial Intelligence-Based Medical Imaging

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSBecause of the growing need to provide better global healthcare, computer-based and robotic healthcare equipment that depend on artificial intelligence have seen an increase in development. In order to evaluate artificial intelligence (AI) in computer technology, the Turing test was created. For evaluating the future generation of medical diagnostics and medical robots, it remains an essential qualitative instrument. MethodWe propose a novel methodology to assess AI-based healthcare technology that provided verifiable diagnostic accuracy and statistical robustness. In order to run our test, we used a State-of-the-art AI model and compared it against radiologist for checking how generalized of the model is and if any biases are prevalent. ResultsWe achieved results that can evaluate the performance of our chosen model for this study in a clinical setting and we also applied a quantifiable methods for evaluating our modified turing test results using a meta-analytical evaluation framework. ConclusionThis test provides a translational standard for upcoming AI modalities. Our modified Turing Test is a notably strong standard to measure the actual performance of the AI model on a variety of edge cases and normal cases and also helps in detecting if the algorithm is biased towards any one type of case. This method extends the flexibility detect any prevalent biases and also classify the type of bias.

bioinformatics↗

bioRxiv2022

ORF6 protein of SARS-CoV-2 inhibits TRIM25 mediated RIG-I ubiquitination to mitigate type I IFN induction.

Evasion and antagonism of host cellular immunity upon SARS-CoV-2 infection confers a profound replication advantage on the virus and contributes to COVID-19 pathogenesis. We explored the ability of different SARS-CoV-2 proteins to antagonize the host innate immune system and found that the ORF6 protein mitigated type-I IFN (interferon) induction and downstream IFN signaling. Our findings also corroborated previous reports that ORF6 blocks the nuclear import of IRF3 and STAT1 to inhibit IFN induction and signaling. Here we show that ORF6 directly interacts with RIG-I and blocks downstream type-I IFN induction and signaling by inhibiting K-63 linked ubiquitination of RIG-I by the E3 Ligase TRIM25. This involves ORF6-mediated targeting of TRIM25 for degradation, also observed during SARS-CoV-2 infection. The type-I IFN antagonistic activity of ORF6 was mapped to its C-terminal cytoplasmic tail, specifically to amino acid residues 52-61. Overall, we provide new insights into how the SARS-CoV-2 ORF6 protein inhibits type I-IFN induction and signaling through distinct mechanisms.

microbiology↗

bioRxiv2022

RADGENNETS: DEEP LEARNING-BASED RADIOGENOMICS MODEL FOR GENE MUTATION PREDICTION IN LUNG CANCER

AO_SCPLOWBSTRACTC_SCPLOWIn this paper, we present our methodology that can be used for predicting gene mutation in patients with non-small cell lung cancer (NSCLC). There are three major types of gene mutations that a NSCLC patients gene structure can change to: epidermal growth factor receptor (EGFR), Kirsten rat sarcoma virus (KRAS), and Anaplastic lymphoma kinase (ALK). We worked with the clinical and genomics data for each patient as well CT scans. We preprocessed all of the data and then built a novel pipeline to integrate both the image and tabular data. We built a novel pipeline that used a fusion of Convolutional Neural Networks and Dense Neural Networks. Also, using a search approach, we pick an ensemble of deep learning models to classify the separate gene mutations. These models include EfficientNets, SENet, and ResNeXt WSL, among others. Our model achieved a high area under curve (AUC) score of 94% in detecting gene mutation.

cancer biology↗

bioRxiv2022

Robust Variation in Infant Gut Microbiome Assembly Across a Spectrum of Lifestyles

Infant microbiome assembly is intensely studied in infants from industrialized nations, but little is known about this process in populations living non-industrialized lifestyles. In this study we deeply sequenced infant stool samples from the Hadza hunter-gatherers of Tanzania and analyzed them in a global meta-analysis. Infant microbiomes develop along lifestyle-associated trajectories, with over twenty percent of genomes detected in the Hadza infant gut representing phylogenetically diverse novel species. Industrialized infants, even those who are breastfed, have microbiomes characterized by a paucity of Bifidobacterium infantis and gene cassettes involved in human milk utilization. Strains within lifestyle-associated taxonomic groups are shared between mother-infant dyads, consistent with early-life inheritance of lifestyle-shaped microbiomes. The population-specific differences in infant microbiome composition and function underscore the importance of studying microbiomes from people outside of wealthy, industrialized nations. Recognition of work on indigenous communitiesResearch involving indigenous communities is needed for a variety of reasons including to ensure that scientific discoveries and understanding appropriately represent all populations and do not only benefit those living in industrialized nations. Special considerations must be made to ensure that this research is conducted ethically and in a non-exploitative manner. In this study we performed deep metagenomic sequencing on fecal samples that were collected from Hadza hunter-gatherers in 2013/2014 and were analyzed in previous publications using different methods (1, 2). A material transfer agreement with the National Institute for Medical Research in Tanzania ensures that stool samples collected are used solely for academic purposes, permission for the study was obtained from the National Institute of Medical Research (MR/53i 100/83, NIMR/HQ/R.8a/Vol.IX/1542) and the Tanzania Commission for Science and Technology, and verbal consent was obtained from the Hadza after the studys intent and scope was described with the help of a translator. The publications that first described these samples included several scientists and Tanzanian field-guides as co-authors for the critical roles they played in sample collection, but as no new samples were collected in this study, only scientists who contributed to the analyses described here were included as co-authors in this publication. It is currently not possible for us to travel to Tanzania and present our results to the Hadza people, however we intend to do so once the conditions of the COVID-19 pandemic allow it.

microbiology↗

bioRxiv2022

Ultra-deep Sequencing of Hadza Hunter-Gatherers Recovers Vanishing Microbes

The gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.

microbiology↗

bioRxiv2022

A natural broad-spectrum inhibitor of enveloped virus entry, effective against SARS-CoV-2 and Influenza A Virus in preclinical animal models.

The COVID-19 pandemic has highlighted the need for novel antivirals for pandemic management and preparedness. Targeting host processes that are co-opted by viruses is an attractive strategy for developing antivirals with a high resistance barrier. Picolinic acid (PA) is a byproduct of tryptophan metabolism, endogenously produced in humans and other mammals. Here we report broad-spectrum antiviral effects of PA against enveloped viruses, including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), Influenza A virus (IAV), Flaviviruses, Herpes Simplex Virus, and Human Parainfluenza Virus. We further demonstrate using animal models that PA is effective against SARS-CoV-2 and IAV, especially as an oral prophylactic. The mode of action studies revealed that PA inhibits viral entry of enveloped viruses, primarily by interfering with viral-cellular membrane fusion, inhibiting virus-mediated syncytia formation, and dysregulating cellular endocytosis. Overall, our data establish PA as a broad-spectrum antiviral agent, with promising preclinical efficacy against pandemic viruses SARS-CoV-2 and IAV.

microbiology↗

bioRxiv2021

Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2

The SARS-Cov-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. The C-terminal helices of Nsp1 (Nsp1-C-ter) from SARS-Cov-2 bind in the mRNA entry channel of the 40S ribosomal subunit and block the entry of mRNAs thereby shutting down host protein synthesis. Nsp1 suppresses the host immune function and is vital for viral replication. Hence, Nsp1 appears to be an attractive target for therapeutics. In this study, we have in silico screened Food and Drug Administration (FDA)-approved drugs against Nsp1-C-ter and find that montelukast sodium hydrate binds to Nsp1-C-ter with a binding affinity (KD) of 10.8{+/-}0.2 M in vitro and forms a stable complex with it in simulation runs with a binding energy of -76.71{+/-}8.95 kJ/mol. The drug also rescues the inhibitory effect of Nsp1 in host protein synthesis as demonstrated by the expression of firefly luciferase reporter gene in cells. Importantly, montelukast sodium hydrate demonstrates antiviral activity against SARS-CoV-2 with reduced viral replication in HEK cells expressing ACE2 and Vero-E6 cells. We therefore propose montelukast sodium hydrate may help in combatting SARS-CoV-2 infection.

biophysics↗

bioRxiv2021

Bronco T (Shirisadi kasaya), a polyherbal formulation ameliorates LPS induced septicemia in rats

Septicemia is a life-threatening state, leading to multi-organ failure, ARDS and death. So, efforts are being made to identify novel therapies. Here, Bronco T (BT), a polyherbal formulation developed in 1984 for treating asthma, has been repurposed against septicemia induced ALI. The LPS (3mg/kg BW) was injected intraperitoneally before 24 hours, of surgery to assess the cardiorespiratory parameters, blood PaO2/FiO2, pulmonary water content and histological changes in the lungs. The pentoxifylline (PTX) (25 mg/kg b.w.) was used as the positive control. The PTX was given one hour before LPS and BT was given 3 hours (orally in different doses of 3, 1.5 and 0.75 gm/kg BW) to maintain the Cmax of the drug. The LPS treated group showed significant bradypnea, bradycardia and low heart rate frequency as observed, through elongated peaks (RR) and (MAP) respectively and finally death after 95 minutes of LPS injection. The PTX and BT (3gm/kg) pretreatment significantly prevented these changes (dose-dependent in the BT group). The survival was maintained up to 190 min after LPS. The Pentoxifylline showed a better response (75%) than Bronco T (72%). In both the treatments, a significant decrease in pulmonary water content and minimal neutrophil infiltration and intact alveoli-capillary membrane was seen in the transverse section (T.S) of the lungs. Conclusion: Significant improvement was noted in survival time, lesser tissue damage and better lung physiology by treating with Bronco T in LPS induced septicemia.

pharmacology and toxicology↗

bioRxiv2021

The MuvB Complex Binds and Stabilizes Nucleosomes Downstream of the Transcription Start Site of Cell-Cycle Dependent Genes

The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. The MuvB TF complex regulates cell-cycle dependent gene-expression and is critical for differentiation and proliferation during development and cancer. MuvB can both positively and negatively regulate expression, but the structure of MuvB and its biochemical function are poorly understood. Here we determine the overall architecture of MuvB assembly and the crystal structure of a subcomplex critical for MuvB function in gene repression. We find that the MuvB subunits LIN9 and LIN37 function as scaffolding proteins that arrange the other subunits LIN52, LIN54 and RBAP48 for TF, DNA, and histone binding, respectively. Biochemical and structural data demonstrate that MuvB binds nucleosomes through an interface that is distinct from LIN54-DNA consensus site recognition and that MuvB increases nucleosome occupancy in a reconstituted promoter. We find in arrested cells that MuvB primarily associates with a tightly positioned +1 nucleosome near the transcription start site (TSS) of MuvB-regulated genes. These results support a model that MuvB binds and stabilizes nucleosomes just downstream of the TSS on its target promoters to repress gene-expression.

molecular biology↗

bioRxiv2021

Genomic Surveillance of COVID-19 Variants with Language Models and Machine Learning

The global efforts to control COVID-19 are threatened by the rapid emergence of novel SARS-CoV-2 variants that may display undesirable characteristics such as immune escape, increased transmissibility or pathogenicity. Early prediction for emergence of new strains with these features is critical for pandemic preparedness. We present Strainflow, a supervised and causally predictive model using unsupervised latent space features of SARS-CoV-2 genome sequences. Strainflow was trained and validated on 0.9 million sequences for the period December, 2019 to June, 2021 and the frozen model was prospectively validated from July, 2021 to December, 2021. Strainflow captured the rise in cases two months ahead of the Delta and Omicron surges in most countries including the prediction of a surge in India as early as beginning of November, 2021. Entropy analysis of Strainflow unsupervised embeddings clearly reveals the explore-exploit cycles in genomic feature-space, thus adding interpretability to the deep learning based model. We also conducted codon-level analysis of our model for interpretability and biological validity of our unsupervised features. Strainflow application is openly available as an interactive web-application for prospective genomic surveillance of COVID-19 across the globe.

bioinformatics↗

bioRxiv2021

Mechanical Interplay Between Transcription Elongation and DNA Supercoiling

Multiple RNA polymerases (RNAPs) transcribing a gene have been known to exhibit collective group behavior, causing the transcription elongation rate to increase with the rate of transcription initiation. Such behavior has long been believed to be driven by a physical interaction or "push" between closely spaced RNAPs. However, recent studies have posited that RNAPs separated by longer distances may cooperate via the DNA segment under transcription. Here, we present a theoretical model incorporating the mechanical coupling between RNAP translocation and the torsional response of supercoiled DNA. Using stochastic simulations, we demonstrate long-range cooperation between co-transcribing RNAPs mediated by DNA supercoiling. We find that inhibiting transcription initiation can slow down the already recruited RNAPs, in agreement with recent experimental observations, and predict that the average transcription elongation rate varies non-monotonically with the rate of transcription initiation. We further show that while RNAPs transcribing neighboring genes oriented in tandem can cooperate, those transcribing genes in divergent or convergent orientations can act antagonistically, and that such behavior holds over a large range of intergenic separations. Our model makes testable predictions, revealing how the mechanical interplay between RNAPs and the DNA they transcribe can govern a key cellular process.

biophysics↗