scholarly journals Global and Gene-specific Transcriptional Responses to Acute Stress

2021 ◽  
Author(s):  
Harry J Fischl ◽  
Thomas Brown ◽  
Andrew Angel ◽  
Jane Mellor
Keyword(s):  
Rna Polymerase Ii ◽  
Acute Stress ◽  
Transcriptional Response ◽  
Transcript Level ◽  
Transcriptional Responses ◽  
Genome Wide ◽  
Degradation Rates ◽  
Response To Stress ◽  
Global Increase ◽  
Yeast Genes

Nucleosomes may regulate transcription by controlling access to promoters by transcription factors and RNA polymerase II (Pol2). Potentially active genes display nucleosome depleted regions flanked by positioned -1 and +1 nucleosomes. On yeast genes, the transcription start site (TSS) is on the upstream face of the +1 nucleosome, but whether precise +1 nucleosome positioning controls Pol2 access to the TSS remains unclear. Here, using acute nutrient starvation to rapidly reprogramme the genome, we show highly dynamic upstream or downstream shifts in the position of +1 nucleosomes, coincident with levels of transcriptionally engaged Pol2 at 58% of genes. Transcript level changes broadly reflect Pol2 occupancy changes with a delay but can be further influenced by Pub1 or Puf3 dependent changes in transcript degradation rates. The response to acute stress has a second component as we also observed genome-wide changes in Pol2 distribution on genes, independent of changes in Pol2 occupancy, with Pol2 accumulating upstream of a +170 nt stalling site. Mathematical modelling supports a global increase in promoter-proximal early transcription termination as a major component of the global stress response. Thus, we uncover a two-component transcriptional response to stress, one focused on the +1 nucleosome, the second on Pol2 itself.

scholarly journals Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages

2018 ◽  
Vol 115 (39) ◽  
pp. E9172-E9181 ◽  
Author(s):  
Aaron F. Carlin ◽  
Edward A. Vizcarra ◽  
Emilie Branche ◽  
Karla M. Viramontes ◽  
Lester Suarez-Amaran ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Zika Virus ◽  
Transcriptional Response ◽  
Lower Sensitivity ◽  
Late Time ◽  
Type I ◽  
Type I Ifn ◽  
Transcriptional Responses ◽  
Preferential Expression ◽  
Genome Wide

Genome-wide investigations of host–pathogen interactions are often limited by analyses of mixed populations of infected and uninfected cells, which lower sensitivity and accuracy. To overcome these obstacles and identify key mechanisms by which Zika virus (ZIKV) manipulates host responses, we developed a system that enables simultaneous characterization of genome-wide transcriptional and epigenetic changes in ZIKV-infected and neighboring uninfected primary human macrophages. We demonstrate that transcriptional responses in ZIKV-infected macrophages differed radically from those in uninfected neighbors and that studying the cell population as a whole produces misleading results. Notably, the uninfected population of macrophages exhibits the most rapid and extensive changes in gene expression, related to type I IFN signaling. In contrast, infected macrophages exhibit a delayed and attenuated transcriptional response distinguished by preferential expression of IFNB1 at late time points. Biochemical and genomic studies of infected macrophages indicate that ZIKV infection causes both a targeted defect in the type I IFN response due to degradation of STAT2 and reduces RNA polymerase II protein levels and DNA occupancy, particularly at genes required for macrophage identity. Simultaneous evaluation of transcriptomic and epigenetic features of infected and uninfected macrophages thereby reveals the coincident evolution of dominant proviral or antiviral mechanisms, respectively, that determine the outcome of ZIKV exposure.

scholarly journals Role of the Hog1 Stress-activated Protein Kinase in the Global Transcriptional Response to Stress in the Fungal PathogenCandida albicans

2006 ◽  
Vol 17 (2) ◽  
pp. 1018-1032 ◽  
Author(s):  
Brice Enjalbert ◽  
Deborah A. Smith ◽  
Michael J. Cornell ◽  
Intikhab Alam ◽  
Susan Nicholls ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heavy Metal ◽  
Protein Kinase ◽  
Transcriptional Response ◽  
Heavy Metal Stress ◽  
Transcriptional Responses ◽  
Stress Genes ◽  
The Core ◽  
Response To Stress

The resistance of Candida albicans to many stresses is dependent on the stress-activated protein kinase (SAPK) Hog1. Hence we have explored the role of Hog1 in the regulation of transcriptional responses to stress. DNA microarrays were used to characterize the global transcriptional responses of HOG1 and hog1 cells to three stress conditions that activate the Hog1 SAPK: osmotic stress, oxidative stress, and heavy metal stress. This revealed both stress-specific transcriptional responses and a core transcriptional response to stress in C. albicans. The core transcriptional response was characterized by a subset of genes that responded in a stereotypical manner to all of the stresses analyzed. Inactivation of HOG1 significantly attenuated transcriptional responses to osmotic and heavy metal stresses, but not to oxidative stress, and this was reflected in the role of Hog1 in the regulation of C. albicans core stress genes. Instead, the Cap1 transcription factor plays a key role in the oxidative stress regulation of C. albicans core stress genes. Our data show that the SAPK network in C. albicans has diverged from corresponding networks in model yeasts and that the C. albicans SAPK pathway functions in parallel with other pathways to regulate the core transcriptional response to stress.

scholarly journals Genome-wide analysis and functional prediction of the estrogen-regulated transcriptional response in the mouse uterus†

2019 ◽  
Vol 102 (2) ◽  
pp. 327-338 ◽  
Author(s):  
Yasmin M Vasquez ◽  
Tulip S Nandu ◽  
Andrew M Kelleher ◽  
Enrique I Ramos ◽  
Shrikanth S Gadad ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Immune Cell ◽  
Expression Profiles ◽  
Transcriptional Response ◽  
Transcriptional Responses ◽  
Mouse Uterus ◽  
Critical Function ◽  
Protein Coding ◽  
Genome Wide ◽  
Genomic Approach

Abstract The ovarian hormones estrogen and progesterone orchestrate the transcriptional programs required to direct functions of the uterus for initiation and maintenance of pregnancy. Estrogen, acting via estrogen receptor alpha, regulates gene expression by activating and repressing distinct genes involved in signaling pathways that regulate cellular and physiological responses including cell division, water influx, and immune cell recruitment. Historically, these transcriptional responses have been postulated to reflect a biphasic physiological response. In this study, we explored the transcriptional responses of the ovariectomized mouse uterus to 17β-estradiol (E2) by RNA-seq to obtain global expression profiles of protein-coding transcripts (mRNAs) and long noncoding RNAs (lncRNAs) following 0.5, 1, 2, and 6 hours of treatment. The E2-regulated mRNA and lncRNA expression profiles in the mouse uterus indicate an association between lncRNAs and mRNAs that regulate E2-driven pathways and reproductive phenotypes in the mouse. The transient E2-regulated transcriptome is reflected in the time-dependent shifting of biological processes regulated in the uterus in response to E2. Moreover, high expression of some conserved lncRNAs that are E2 regulated in the mouse uterus are predictive of low overall survival in endometrial carcinoma patients (e.g., H19, KCNQ1OT1, MIR17HG, and FTX). Collectively, this study (1) describes a genomic approach for identifying E2-regulated lncRNAs that may serve critical function in the uterus and (2) provides new insights into our understanding of the regulation of hormone-regulated transcriptional responses with implications in pregnancy and endometrial pathologies.

scholarly journals CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

2020 ◽  
Vol 6 (18) ◽  
pp. eaaz5041 ◽  
Author(s):  
Zheng Fan ◽  
Jennifer R. Devlin ◽  
Simon J. Hogg ◽  
Maria A. Doyle ◽  
Paul F. Harrison ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Cellular Growth ◽  
Transcriptional Elongation ◽  
Transcriptional Responses ◽  
Kinase Inhibition ◽  
Homology Directed Repair ◽  
Molecular Events ◽  
Genome Wide ◽  
Transcriptional Changes

The RNA polymerase II (POLII)–driven transcription cycle is tightly regulated at distinct checkpoints by cyclin-dependent kinases (CDKs) and their cognate cyclins. The molecular events underpinning transcriptional elongation, processivity, and the CDK-cyclin pair(s) involved remain poorly understood. Using CRISPR-Cas9 homology-directed repair, we generated analog-sensitive kinase variants of CDK12 and CDK13 to probe their individual and shared biological and molecular roles. Single inhibition of CDK12 or CDK13 induced transcriptional responses associated with cellular growth signaling pathways and/or DNA damage, with minimal effects on cell viability. In contrast, dual kinase inhibition potently induced cell death, which was associated with extensive genome-wide transcriptional changes including widespread use of alternative 3′ polyadenylation sites. At the molecular level, dual kinase inhibition resulted in the loss of POLII CTD phosphorylation and greatly reduced POLII elongation rates and processivity. These data define substantial redundancy between CDK12 and CDK13 and identify both as fundamental regulators of global POLII processivity and transcription elongation.

scholarly journals Remodeling of Yeast Genome Expression in Response to Environmental Changes

2001 ◽  
Vol 12 (2) ◽  
pp. 323-337 ◽  
Author(s):  
Helen C. Causton ◽  
Bing Ren ◽  
Sang Seok Koh ◽  
Christopher T. Harbison ◽  
Elenita Kanin ◽  
...  
Keyword(s):  
Environmental Change ◽  
Expression Analysis ◽  
Environmental Changes ◽  
Transcriptional Response ◽  
Yeast Genome ◽  
Temperature Oxidation ◽  
Genome Wide ◽  
Environmental Responses ◽  
Yeast Genes ◽  
Response To Environmental Change

We used genome-wide expression analysis to explore how gene expression in Saccharomyces cerevisiae is remodeled in response to various changes in extracellular environment, including changes in temperature, oxidation, nutrients, pH, and osmolarity. The results demonstrate that more than half of the genome is involved in various responses to environmental change and identify the global set of genes induced and repressed by each condition. These data implicate a substantial number of previously uncharacterized genes in these responses and reveal a signature common to environmental responses that involves ∼10% of yeast genes. The results of expression analysis with MSN2/MSN4 mutants support the model that the Msn2/Msn4 activators induce the common response to environmental change. These results provide a global description of the transcriptional response to environmental change and extend our understanding of the role of activators in effecting this response.

scholarly journals ASXL1 Directs Neutrophilic Differentiation via Modulation of MYC and RNA Polymerase II.

2020 ◽  
Author(s):  
Theodore P Braun ◽  
Joseph Estabrook ◽  
Daniel J Coleman ◽  
Zachary Schonrock ◽  
Brittany M Smith ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Myeloid Malignancies ◽  
Polycomb Repressive Complex 2 ◽  
Genome Wide ◽  
Sex Combs ◽  
Epigenetic Regulator ◽  
Additional Sex Combs ◽  
Global Increase

Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. An epigenetic regulator, ASXL1 ca-nonically directs the deposition of H3K27me3 via the polycomb repressive complex 2. However, its precise role in myeloid lineage maturation is incompletely described. We utilized single cell RNA sequencing (scRNA-seq) on a murine model of hematopoietic-specific ASXL1 deletion and identified a specific role for ASXL1 in terminal granulo-cyte maturation. Terminal maturation is accompanied by down regulation of Myc ex-pression and cell cycle exit. ASXL1 deletion leads to hyperactivation of Myc in granu-locyte precursors and a quantitative decrease in neutrophil production. This failure of normal developmentally-associated Myc suppression is not accompanied by signifi-cant changes in the landscape of covalent histone modifications including H3K27me3. Examining the genome-wide localization of ASXL1 in myeloid progenitors revealed strong co-localization with RNA Polymerase II (RNAPII) at the promoters and spread across the gene bodies of transcriptionally active genes. ASXL1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription, consistent with the known role of ASXL1 as a mediator of RNAPII pause release. These results suggest that ASXL1 in-hibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator and highlighting a novel potential oncogenic mechanism for ASXL1 mutations in myeloid malignancies.

scholarly journals Gene regulation gravitates towards either addition or multiplication when combining the effects of two signals

2020 ◽  
Author(s):  
Eric M. Sanford ◽  
Benjamin L. Emert ◽  
Allison Coté ◽  
Arjun Raj
Keyword(s):  
Transcriptional Response ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Mechanistic Models ◽  
Transcriptional Responses ◽  
Genome Wide ◽  
Putative Transcription Factor ◽  
The Individual ◽  
Transcription Factor Occupancy ◽  
Mcf 7

AbstractSignals often ultimately affect the transcription of genes, and often, two different signals can affect the transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. Mechanistic models can predict a range of combined responses, with the most commonly applied models predicting additive or multiplicative responses, but systematic genome-wide evaluation of these predictions are not available. Here, we performed a comprehensive analysis of the transcriptional response of human MCF-7 cells to two different signals (retinoic acid and TGF-β), applied individually and in combination. We found that the combined responses exhibited a range of behaviors, but clearly favored both additive and multiplicative combined transcriptional responses. We also performed paired chromatin accessibility measurements to measure putative transcription factor occupancy at regulatory elements near these genes. We found that increases in chromatin accessibility were largely additive, meaning that the combined accessibility response was the sum of the accessibility responses to each signal individually. We found some association between super-additivity of accessibility and multiplicative or super-multiplicative combined transcriptional responses, while sub-additivity of accessibility associated with additive transcriptional responses. Our findings suggest that mechanistic models of combined transcriptional regulation must be able to reproduce a range of behaviors.

scholarly journals Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

2016 ◽  
Vol 113 (36) ◽  
pp. 9967-9976 ◽  
Author(s):  
Supipi Duffy ◽  
Hok Khim Fam ◽  
Yi Kan Wang ◽  
Erin B. Styles ◽  
Jung-Hyun Kim ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Human Cancer ◽  
Trichostatin A ◽  
Chromosome Instability ◽  
Human Cells ◽  
Gene Overexpression ◽  
Genome Wide ◽  
Yeast Genes

Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes,TDP1, a tyrosyl-DNA-phosphdiesterase, andTAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown ofTDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylaseRPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.

scholarly journals Temporal transcriptional response of Candida glabrata during macrophage infection reveals a multifaceted transcriptional regulator CgXbp1 important for macrophage response and drug resistance

2021 ◽  
Author(s):  
Maruti Nandan Rai ◽  
Chirag Parsania ◽  
Rikky Rai ◽  
Niranjan Shirgaonkar ◽  
Kaeling Tan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factor ◽  
Rna Polymerase Ii ◽  
Candida Glabrata ◽  
Drug Tolerance ◽  
High Temporal Resolution ◽  
Macrophage Infection ◽  
Transcriptional Responses ◽  
Macrophage Response ◽  
Genome Wide

AbstractCandida glabrata can thrive inside macrophages and tolerate high levels of azole antifungals. These innate abilities render infections by this human pathogen a clinical challenge. How C. glabrata reacts inside macrophages and what is the molecular basis of its drug tolerance are not well understood. Here, we mapped genome-wide RNA polymerase II (RNAPII) occupancy in C. glabrata to delineate its transcriptional responses during macrophage infection in high temporal resolution. RNAPII profiles revealed dynamic C. glabrata responses to macrophage with genes of specialized pathways activated chronologically at different times of infection. We identified an uncharacterized transcription factor (CgXbp1) important for the chronological macrophage response, survival in macrophages, and virulence. Genome-wide mapping of CgXbp1 direct targets further revealed its multi-faceted functions, regulating not only virulence-related genes but also genes associated with drug resistance. Finally, we showed that CgXbp1 indeed also affects azole resistance. Overall, this work presents a powerful approach for examining host-pathogen interaction and uncovers a novel transcription factor important for C. glabrata’s survival in macrophages and drug tolerance.

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