scholarly journals Global Transcriptional Response of Methylorubrum extorquens to Formaldehyde Stress Expands the Role of EfgA and Is Distinct from Antibiotic Translational Inhibition

2021 ◽  
Vol 9 (2) ◽  
pp. 347
Author(s):  
Jannell V. Bazurto ◽  
Siavash Riazi ◽  
Simon D’Alton ◽  
Daniel E. Deatherage ◽  
Eric L. Bruger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Carbon Source ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Biological Molecules ◽  
Regulatory Control ◽  
Translation Inhibition ◽  
Translational Inhibition ◽  
Potential Carbon

The potency and indiscriminate nature of formaldehyde reactivity upon biological molecules make it a universal stressor. However, some organisms such as Methylorubrum extorquens possess means to rapidly and effectively mitigate formaldehyde-induced damage. EfgA is a recently identified formaldehyde sensor predicted to halt translation in response to elevated formaldehyde as a means to protect cells. Herein, we investigate growth and changes in gene expression to understand how M. extorquens responds to formaldehyde with and without the EfgA-formaldehyde-mediated translational response, and how this mechanism compares to antibiotic-mediated translation inhibition. These distinct mechanisms of translation inhibition have notable differences: they each involve different specific players and in addition, formaldehyde also acts as a general, multi-target stressor and a potential carbon source. We present findings demonstrating that in addition to its characterized impact on translation, functional EfgA allows for a rapid and robust transcriptional response to formaldehyde and that removal of EfgA leads to heightened proteotoxic and genotoxic stress in the presence of increased formaldehyde levels. We also found that many downstream consequences of translation inhibition were shared by EfgA-formaldehyde- and kanamycin-mediated translation inhibition. Our work uncovered additional layers of regulatory control enacted by functional EfgA upon experiencing formaldehyde stress, and further demonstrated the importance this protein plays at both transcriptional and translational levels in this model methylotroph.

scholarly journals Global transcriptional response of Methylorubrum extorquens to formaldehyde stress expands the role of EfgA and is distinct from antibiotic translational inhibition

2021 ◽  
Author(s):  
Jannell Bazurto ◽  
Siavash Riazi ◽  
Simon D'Alton ◽  
Daniel E. Deatherage ◽  
Eric L. Bruger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Carbon Source ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Biological Molecules ◽  
Regulatory Control ◽  
Translation Inhibition ◽  
Translational Inhibition ◽  
Potential Carbon

The potency and indiscriminate nature of formaldehyde reactivity upon biological molecules make it a universal stressor. However, some organisms such as Methylorubrum extorquens possess means to rapidly and effectively mitigate formaldehyde-induced damage. EfgA is a recently identified formaldehyde sensor predicted to halt translation in response to elevated formaldehyde as a means to protect cells. Herein, we investigate growth and changes in gene expression to understand how M. extorquens responds to formaldehyde with and without the EfgA-formaldehyde-mediated translational response, and how this mechanism compares to antibiotic-mediated translation inhibition. These distinct mechanisms of translation inhibition have notable differences: they each involve different specific players and in addition, formaldehyde also acts as a general, multi-target stressor and a potential carbon source. We present findings demonstrating that in addition to its characterized impact on translation, functional EfgA allows for a rapid and robust transcriptional response to formaldehyde and that removal of EfgA leads to heightened proteotoxic and genotoxic stress in the presence of increased formaldehyde levels. We also found that many downstream consequences of translation inhibition were shared by EfgA-formaldehyde- and kanamycin-mediated translation inhibition. Our work uncovered additional layers of regulatory control enacted by functional EfgA upon experiencing formaldehyde stress, and further demonstrated the importance this protein plays at both transcriptional and translational levels in this model methylotroph.

scholarly journals Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Genes ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 19 ◽  
Author(s):  
Harmen Hawer ◽  
Alexander Hammermeister ◽  
Keerthiraju Ravichandran ◽  
Sebastian Glatt ◽  
Raffael Schaffrath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Disease ◽  
Messenger Rna ◽  
Environmental Changes ◽  
Mrna Translation ◽  
Regulatory Control ◽  
Trna Modification ◽  
Positive Role ◽  
Trna Modifications

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

scholarly journals Interplay of a Ligand Sensor and an Enzyme in Controlling Expression of the Saccharomyces cerevisiae GAL Genes

2011 ◽  
Vol 11 (3) ◽  
pp. 334-342 ◽  
Author(s):  
Dariusz Abramczyk ◽  
Stacey Holden ◽  
Christopher J. Page ◽  
Richard J. Reece
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Transcriptional Control ◽  
Transcriptional Response ◽  
Content Type ◽  
Considerable Debate ◽  
Active Transcription ◽  
Gal Genes ◽  
The Subject

ABSTRACT The regulation of the Saccharomyces cerevisiae GAL genes in response to galactose as a source of carbon has served as a paradigm for eukaryotic transcriptional control over the last 50 years. Three proteins—a transcriptional activator (Gal4p), an inhibitor (Gal80p), and a ligand sensor (Gal3p)—control the switch between inert and active gene expression. The molecular mechanism by which the recognition of galactose within the cell is converted into a transcriptional response has been the subject of considerable debate. In this study, using a novel and powerful method of localizing active transcription factors within the nuclei of cells, we show that a short-lived complex between Gal4p, Gal80p, and Gal3p occurs soon after the addition of galactose to cells to activate GAL gene expression. Gal3p is subsequently replaced in this complex by Gal1p, and a Gal4p-Gal80p-Gal1p complex is responsible for the continued expression of the GAL genes. The transient role of the ligand sensor indicates that current models for the induction and continued expression of the yeast GAL genes need to be reevaluated.

scholarly journals p53-dependent induction of P2X7 on hematopoietic stem and progenitor cells regulates hematopoietic response to genotoxic stress

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Lin Tze Tung ◽  
HanChen Wang ◽  
Jad I. Belle ◽  
Jessica C. Petrov ◽  
David Langlais ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Whole Body ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Stem And Progenitor Cells ◽  
Hematopoietic Response

AbstractStem and progenitor cells are the main mediators of tissue renewal and repair, both under homeostatic conditions and in response to physiological stress and injury. Hematopoietic system is responsible for the regeneration of blood and immune cells and is maintained by bone marrow-resident hematopoietic stem and progenitor cells (HSPCs). Hematopoietic system is particularly susceptible to injury in response to genotoxic stress, resulting in the risk of bone marrow failure and secondary malignancies in cancer patients undergoing radiotherapy. Here we analyze the in vivo transcriptional response of HSPCs to genotoxic stress in a mouse whole-body irradiation model and, together with p53 ChIP-Seq and studies in p53-knockout (p53KO) mice, characterize the p53-dependent and p53-independent branches of this transcriptional response. Our work demonstrates the p53-independent induction of inflammatory transcriptional signatures in HSPCs in response to genotoxic stress and identifies multiple novel p53-target genes induced in HSPCs in response to whole-body irradiation. In particular, we establish the direct p53-mediated induction of P2X7 expression on HSCs and HSPCs in response to genotoxic stress. We further demonstrate the role of P2X7 in hematopoietic response to acute genotoxic stress, with P2X7 deficiency significantly extending mouse survival in irradiation-induced hematopoietic failure. We also demonstrate the role of P2X7 in the context of long-term HSC regenerative fitness following sublethal irradiation. Overall our studies provide important insights into the mechanisms of HSC response to genotoxic stress and further suggest P2X7 as a target for pharmacological modulation of HSC fitness and hematopoietic response to genotoxic injury.

scholarly journals O-GlcNAc regulates MTA1 transcriptional activity during breast cancer cells genotoxic adaptation

2021 ◽  
Author(s):  
Xueqin Xie ◽  
Qiutong Wu ◽  
Keren Zhang ◽  
Yimin Liu ◽  
Nana Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcriptional Regulation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Genotoxic Stress ◽  
Histone Deacetylation ◽  
Nurd Complex ◽  
Nucleosome Remodeling

AbstractChromatin modifier metastasis-associated protein 1 (MTA1), closely correlated with the development and progression in breast cancer, has a vital role in multiple cellular processes, including gene expression and cell homeostasis. Although MTA1 is a stress-responsive gene, its role in genotoxic adaptation remains unexplored. The current study sought to investigate the role of MTA1 and its O-GlcNAc modification in breast cancer cells genotoxic adaptation by using quantitative proteomics, ChIP-seq, transcriptome analysis, loss-and gain-of-functions experiments. We demonstrate that O-GlcNAc modification promotes MTA1 to interact with chromatin and regulates target gene expression, contributing to breast cancer cell genotoxic adaptation. MTA1 is modified with O-GlcNAc residues at serine 237/241/246 in adriamycin adaptive breast cancer cells and that modification improves the genome-wide interactions of MTA1 with gene promotor regions by enhancing its association with nucleosome remodeling and histone deacetylation (NuRD) complex. Further, O-GlcNAc-modulated MTA1 chromatin-binding influences the specific transcriptional regulation of genes involved in the adaptation of breast cancer cells to genotoxic stress. Our findings reveal a previously unrecognized role of O-GlcNAc MTA1 in transcriptional regulation and suggest that O-GlcNAc modification is a promising therapeutic target to overcome chemoresistance in breast cancers.

scholarly journals Insulation of gene expression by CTCF and cohesin-based subTAD (ubiquitous intra-TAD) loop structures in mouse liver

2018 ◽  
Author(s):  
Bryan J. Matthews ◽  
David J. Waxman
Keyword(s):  
Gene Expression ◽  
Nuclear Organization ◽  
Computational Method ◽  
Regulatory Control ◽  
Ctcf Binding ◽  
Distal Enhancer ◽  
Repressive Histone Mark ◽  
Extrusion Mechanism ◽  
Functional Features

ABSTRACTCTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present a computational method to identify cohesin-and-CTCF binding sites that form intra-TAD DNA loops (subTADs). We show that predicted subTAD anchors are structurally indistinguishable from those of TADs regarding their binding partners, sequence conservation, and resistance to cohesin knockdown; further, the subTAD loops retain key functional features of TADs, including insulation of chromatin contacts, blockage of repressive histone mark spread, and ubiquity across tissues. We propose that subTADs form by the same loop extrusion mechanism as larger loops, and that their shorter length enables finer regulatory control over gene expression. 4C-seq analysis using an Alb promoter viewpoint illustrates the role of subTADs in restricting enhancer-promoter interactions. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization, and demonstrate that distal enhancer insulation by subTADs is widespread.

scholarly journals Role of the cellular protein hDaxx in human cytomegalovirus immediate-early gene expression

2006 ◽  
Vol 87 (5) ◽  
pp. 1113-1121 ◽  
Author(s):  
Chris M. Preston ◽  
Mary Jane Nicholl
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Transcriptional Response ◽  
Cellular Protein ◽  
Early Gene ◽  
Immediate Early ◽  
Simplex Virus ◽  
Interfering Rna ◽  
Stimulation Of

Human cytomegalovirus (HCMV) immediate-early (IE) transcription is stimulated by virion phosphoprotein pp71, the product of gene UL82. It has previously been shown that pp71 interacts with the cellular protein hDaxx and, in the studies presented here, the significance of this interaction was investigated for HCMV IE gene expression. In co-transfection experiments, the presence of hDaxx increased the transcriptional response of the HCMV major IE promoter (MIEP) to pp71, but it was not possible to determine whether the effect was due to an interaction between the two proteins or to stimulation of hDaxx synthesis by pp71. The use of small interfering RNA (siRNA) in long- and short-term transfection approaches reduced intracellular hDaxx levels to no more than 3 % of normal. Infection of hDaxx-depleted cells with herpes simplex virus recombinants containing the HCMV MIEP revealed significantly greater promoter activity when hDaxx levels were minimal. Similarly, reducing intracellular hDaxx amounts resulted in greater IE gene expression during infection with an HCMV mutant lacking pp71, but had no effect on IE transcription during infection with wild-type HCMV. The results suggest that hDaxx is not important as a positive-acting factor for the stimulation of HCMV IE transcription by pp71. Instead, it appears that hDaxx acts as a repressor of IE gene expression, and it is proposed here that the interaction of pp71 with hDaxx is important to relieve repression and permit efficient initiation of productive replication.

scholarly journals Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders

2019 ◽  
Author(s):  
D Nachun ◽  
EM Ramos ◽  
A Karydas ◽  
D Dokuru ◽  
F Gao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Response ◽  
Peripheral Blood ◽  
Transcriptional Response ◽  
Innate Immune ◽  
Blood Gene Expression ◽  
Dementia Patients ◽  
Peripheral Blood Gene Expression ◽  
Level Analysis

AbstractThe role of peripheral inflammation in dementia is an important but complex topic. We present here the largest cohort of peripheral blood gene expression data ever assembled from patients with dementia and matching controls. Importantly, this cohort includes individuals from a diverse set of dementia disorders, including Alzheimer’s Disease (AD), mild cognitive impairment (MCI), and multiple disorders within the frontotemporal dementia (FTD) spectrum. We found strong transcriptional evidence of an innate immune inflammatory response, mediated by monocytes and neutrophils, in AD, MCI, and two FTD subtypes, PSP and nfvPPA. This transcriptional inflammatory response is enriched for genetic risk for AD, in part because it is also enriched for microglial genes, which have previously been implicated in AD risk. Finally, we show that this transcriptional response is strongly enriched for binding of the transcription factors PU.1 and RELA, which have previously been linked to AD risk and progression.

Role of small nuclear RNAs in eukaryotic gene expression

2013 ◽  
Vol 54 ◽  
pp. 79-90 ◽  
Author(s):  
Saba Valadkhan ◽  
Lalith S. Gunawardane
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Rna Stability ◽  
Splice Sites ◽  
Branch Site ◽  
Small Nuclear Rnas ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Rna Biogenesis

Eukaryotic cells contain small, highly abundant, nuclear-localized non-coding RNAs [snRNAs (small nuclear RNAs)] which play important roles in splicing of introns from primary genomic transcripts. Through a combination of RNA–RNA and RNA–protein interactions, two of the snRNPs, U1 and U2, recognize the splice sites and the branch site of introns. A complex remodelling of RNA–RNA and protein-based interactions follows, resulting in the assembly of catalytically competent spliceosomes, in which the snRNAs and their bound proteins play central roles. This process involves formation of extensive base-pairing interactions between U2 and U6, U6 and the 5′ splice site, and U5 and the exonic sequences immediately adjacent to the 5′ and 3′ splice sites. Thus RNA–RNA interactions involving U2, U5 and U6 help position the reacting groups of the first and second steps of splicing. In addition, U6 is also thought to participate in formation of the spliceosomal active site. Furthermore, emerging evidence suggests additional roles for snRNAs in regulation of various aspects of RNA biogenesis, from transcription to polyadenylation and RNA stability. These snRNP-mediated regulatory roles probably serve to ensure the co-ordination of the different processes involved in biogenesis of RNAs and point to the central importance of snRNAs in eukaryotic gene expression.

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