scholarly journals The Clock Takes Shape—24 h Dynamics in Genome Topology

2022 ◽  
Vol 9 ◽  
Author(s):  
Kévin Tartour ◽  
Kiran Padmanabhan
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Cellular Level ◽  
Damage Response ◽  
And Behavior ◽  
Open Question ◽  
Daily Changes

Circadian rhythms orchestrate organismal physiology and behavior in order to anticipate daily changes in the environment. Virtually all cells have an internal rhythm that is synchronized every day by Zeitgebers (environmental cues). The synchrony between clocks within the animal enables the fitness and the health of organisms. Conversely, disruption of rhythms is linked to a variety of disorders: aging, cancer, metabolic diseases, and psychological disorders among others. At the cellular level, mammalian circadian rhythms are built on several layers of complexity. The transcriptional-translational feedback loop (TTFL) was the first to be described in the 90s. Thereafter oscillations in epigenetic marks highlighted the role of chromatin state in organizing the TTFL. More recently, studies on the 3D organization of the genome suggest that genome topology could be yet another layer of control on cellular circadian rhythms. The dynamic nature of genome topology over a solar day implies that the 3D mammalian genome has to be considered in the fourth dimension-in time. Whether oscillations in genome topology are a consequence of 24 h gene-expression or a driver of transcriptional cycles remains an open question. All said and done, circadian clock-gated phenomena such as gene expression, DNA damage response, cell metabolism and animal behavior—go hand in hand with 24 h rhythms in genome topology.

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

2019 ◽  
Vol 105 (3) ◽  
pp. 839-853
Author(s):  
Aglaia Kyrilli ◽  
David Gacquer ◽  
Vincent Detours ◽  
Anne Lefort ◽  
Frédéric Libert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Iodide Uptake ◽  
Transcriptomic Response ◽  
Uptake Inhibition ◽  
Γ Radiation ◽  
Damage Response

Abstract Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure. Conclusions TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.

scholarly journals Glucocorticoid receptor action in metabolic and neuronal function

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1208 ◽  
Author(s):  
Michael J. Garabedian ◽  
Charles A. Harris ◽  
Freddy Jeanneteau
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Metabolic Diseases ◽  
Cell Types ◽  
Health And Disease ◽  
And Behavior ◽  
External Signals ◽  
The Brain

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this “brain-fat axis” will enable a more complete understanding of metabolic diseases and inform new ways to target them.

Insights Into the Role of ASPP2 (Apoptosis Stimulating Protein of p53-2) in Lymphomagenesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1967-1967
Author(s):  
Kerstin M Kampa ◽  
Sandra Mueller ◽  
Michael Bonin ◽  
Marcus M Schittenhelm ◽  
Charles D Lopez
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
T Cell ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Target Genes ◽  
Tumor Formation ◽  
Transcriptional Networks ◽  
Damage Response

Abstract Abstract 1967 Poster Board I-990 ASPP2 is a member of a family of p53 binding proteins that enhance apoptosis, in part through selective stimulation of p53 transactivation of pro-apoptotic target genes. Low ASPP2 expression is found in many human cancers and has been associated with poor clinical outcome in patients with aggressive lymphoma. Using an ASPP2+/- mouse model, we have previously demonstrated that ASPP2 is a haploinsufficient tumor suppressor and that reduced ASPP2 expression results in attenuated damage-response thresholds (Kampa et al., PNAS 2009). While ASPP2-/- mice are not viable, ASPP2+/- mice have an increased incidence of -irradiation-induced tumors compared to ASPP2+/+ mice.γspontaneous and ASPP2+/- mice develop high-grade thymic T-cell lymphomas after -irradiation. Moreover, primary ASPP2+/- thymocytes have an attenuatedγ -irradiation compared to ASPP2+/+ thymocytes.γapoptotic response after To explore the mechanisms of how attenuated ASPP2 expression could increase thymic lymphomagenesis and attenuate apoptosis, we performed global gene expression profiling on unirradiated, and 5 Gy irradiated ASPP2+/+ and ASPP2+/- thymocytes using an Affymetrix Mouse GeneChip® Array. We found significant differences in gene expression between ASPP2+/+ and ASPP2+/- thymocytes, in both unirradiated and irradiated sets. Using Ingenuity Pathway Analysis software, we found that amongst the highest scoring pathways displaying differences were those associated with cell growth, tumor formation, hematologic malignancies, immune response, cell death and cell cycle regulation. We additionally studied global phosphorylation patterns using 2-dimensional gel electrophoresis, fluorescent phosphoprotein dye Pro-Q Diamond staining, and liquid chromatography tandem mass spectrometry to determine the posttranscriptional mechanisms mediated by attenuated ASPP2 expression. Analysis of the phosphoproteome of ASPP2+/+ and ASPP2+/- mouse embryonic fibroblasts (with and without irradiation) revealed differences in the phosphorylation status of 108 peptides/proteins including those involved in regulating cell cycle checkpoints, T-cell receptor signaling, cell stress response, DNA repair mechanisms, cell growth, translation and transcription. Differential expression of the identified genes and proteins was verified by PCR and Western Blot. Thus, reduced ASPP2 expression affects global transcriptional as well as post-transcriptional networks intimately involved in the development of hematologic disorders–suggesting that ASPP2 function is by far more complex than solely enhancing the expression of pro-apoptotic p53 target genes. Given that ASPP2 is a bona fide tumor suppressor, reduced ASPP2 levels result in global dysregulation of pathways engaged in tumor suppression networks and the cellular damage response, which may ultimately promote genomic instability and tumor formation. Our findings provide insights into the role of ASPP2 in lymphomagenesis and reveal possible new targets for cancer therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Does a Red House Affect Rhythms in Mice with a Corrupted Circadian System?

2021 ◽  
Vol 22 (5) ◽  
pp. 2288
Author(s):  
Menekse Öztürk ◽  
Marc Ingenwerth ◽  
Martin Sager ◽  
Charlotte von Gall ◽  
Amira A. H. Ali
Keyword(s):  
Circadian Rhythms ◽  
Neuronal Activity ◽  
Clock Genes ◽  
Plasma Corticosterone ◽  
Cellular Level ◽  
Circadian System ◽  
Targeted Deletion ◽  
Long Wavelength ◽  
And Behavior ◽  
Time Information

The circadian rhythms of body functions in mammals are controlled by the circadian system. The suprachiasmatic nucleus (SCN) in the hypothalamus orchestrates subordinate oscillators. Time information is conveyed from the retina to the SCN to coordinate an organism’s physiology and behavior with the light/dark cycle. At the cellular level, molecular clockwork composed of interlocked transcriptional/translational feedback loops of clock genes drives rhythmic gene expression. Mice with targeted deletion of the essential clock gene Bmal1 (Bmal1−/−) have an impaired light input pathway into the circadian system and show a loss of circadian rhythms. The red house (RH) is an animal welfare measure widely used for rodents as a hiding place. Red plastic provides light at a low irradiance and long wavelength—conditions which affect the circadian system. It is not known yet whether the RH affects rhythmic behavior in mice with a corrupted circadian system. Here, we analyzed whether the RH affects spontaneous locomotor activity in Bmal1−/− mice under standard laboratory light conditions. In addition, mPER1- and p-ERK-immunoreactions, as markers for rhythmic SCN neuronal activity, and day/night plasma corticosterone levels were evaluated. Our findings indicate that application of the RH to Bmal1−/− abolishes rhythmic locomotor behavior and dampens rhythmic SCN neuronal activity. However, RH had no effect on the day/night difference in corticosterone levels.

scholarly journals Thrombospondin 1 in Metabolic Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Linda S. Gutierrez ◽  
Jovita Gutierrez
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Matricellular Protein ◽  
Published Data ◽  
Obesity And Diabetes ◽  
Thrombospondin 1 ◽  
Cancer And Inflammation

The thrombospondin family comprises of five multifunctional glycoproteins, whose best-studied member is thrombospondin 1 (TSP1). This matricellular protein is a potent antiangiogenic agent that inhibits endothelial migration and proliferation, and induces endothelial apoptosis. Studies have demonstrated a regulatory role of TSP1 in cell migration and in activation of the latent transforming growth factor beta 1 (TGFβ1). These functions of TSP1 translate into its broad modulation of immune processes. Further, imbalances in immune regulation have been increasingly linked to pathological conditions such as obesity and diabetes mellitus. While most studies in the past have focused on the role of TSP1 in cancer and inflammation, recently published data have revealed new insights about the role of TSP1 in physiological and metabolic disorders. Here, we highlight recent findings that associate TSP1 and its receptors to obesity, diabetes, and cardiovascular diseases. TSP1 regulates nitric oxide, activates latent TGFβ1, and interacts with receptors CD36 and CD47, to play an important role in cell metabolism. Thus, TSP1 and its major receptors may be considered a potential therapeutic target for metabolic diseases.

scholarly journals Non-Genomic Control of Dynamic MYCN Gene Expression in Liver Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Xian-Yang Qin ◽  
Luc Gailhouste
Keyword(s):  
Gene Expression ◽  
Liver Cancer ◽  
Dna Amplification ◽  
Predictive Biomarker ◽  
Cellular Level ◽  
Diagnostic Strategies ◽  
Lipid Desaturation ◽  
Tumor Suppressive Mirnas ◽  
Post Transcriptional Regulation

Upregulated MYCN gene expression is restricted to specialized cell populations such as EpCAM+ cancer stem cells in liver cancer, regardless of DNA amplification and mutation. Here, we reviewed the role of MYCN gene expression in liver homeostasis, regeneration, and tumorigenesis, and discussed the potential non-genomic mechanisms involved in controlling MYCN gene expression in liver cancer, with a focus on inflammation-mediated signal transduction and microRNA-associated post-transcriptional regulation. We concluded that dynamic MYCN gene expression is an integrated consequence of multiple signals in the tumor microenvironment, including tumor growth-promoting signals, lipid desaturation-mediated endoplasmic reticulum stress adaptation signals, and tumor suppressive miRNAs, making it a potential predictive biomarker of tumor stemness and plasticity. Therefore, understanding and tracing the dynamic changes and functions of MYCN gene expression will shed light on the origin of liver tumorigenesis at the cellular level and the development of novel therapeutic and diagnostic strategies for liver cancer treatment.

scholarly journals The queen, but not the brood, drives early changes in brain gene expression in bumble bee workers 

2021 ◽  
Author(s):  
Priscila Santos ◽  
Jesse Starkey ◽  
David Galbraith ◽  
Etya Amsalem
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Egg Laying ◽  
Differentially Expressed ◽  
Bumble Bee ◽  
Brood Care ◽  
Brain Gene Expression ◽  
Evolution Of Sociality ◽  
And Behavior

Worker reproduction in social insects is often regulated by the queen, but can be regulated by the brood and nestmates, who may use different mechanisms to induce the same outcomes in subordinates. Analysis of brain gene expression patterns in bumble bee workers (Bombus impatiens) in response to the presence of the queen, the brood, both or neither, identified 18 differentially expressed genes, 17 of them are regulated by the queen and none are regulated by the brood. Overall, brain gene expression differences in workers were driven by the queen’s presence, despite recent studies showing that brood reduces worker egg laying and provides context to the queen pheromones. The queen affected important regulators of reproduction and brood care across insects, such as neuroparsin and vitellogenin, and a comparison with similar datasets in the honey bee and the clonal raider ant revealed that neuroparsin is differentially expressed in all species. These data emphasize the prominent role of the queen in regulating worker physiology and behavior. Genes that serve as key regulators of workers’ reproduction are likely to play an important role in the evolution of sociality.

Circadian Rhythms, Disease and Chronotherapy

2021 ◽  
pp. 074873042110443
Author(s):  
Yool Lee ◽  
Jeffrey M. Field ◽  
Amita Sehgal
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clocks ◽  
Cellular Mechanisms ◽  
Medical Interventions ◽  
Timing Mechanisms ◽  
Parasite Infections ◽  
Circadian Physiology ◽  
And Behavior ◽  
Internal Body

Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and metabolism. The adaptive value of clocks is evident when internal body clocks and daily environmental cycles are mismatched, such as in the case of shift work and jet lag or even mistimed eating, all of which are associated with physiological disruption and disease. Studies with animal and human models have also unraveled an important role of functional circadian clocks in modulating cellular and organismal responses to physiological cues (ex., food intake, exercise), pathological insults (e.g. virus and parasite infections), and medical interventions (e.g. medication). With growing knowledge of the molecular and cellular mechanisms underlying circadian physiology and pathophysiology, it is becoming possible to target circadian rhythms for disease prevention and treatment. In this review, we discuss recent advances in circadian research and the potential for therapeutic applications that take patient circadian rhythms into account in treating disease.

Energy metabolism and cytochrome oxidase activity: linking metabolism to gene expression

2014 ◽  
Vol 92 (7) ◽  
pp. 557-568 ◽  
Author(s):  
K. Bremer ◽  
K.M. Kocha ◽  
T. Snider ◽  
C.D. Moyes
Keyword(s):  
Gene Expression ◽  
Metabolic Diseases ◽  
Mitochondrial Gene ◽  
Metabolic Phenotype ◽  
Post Translational Modification ◽  
Master Regulators ◽  
Evolutionary Origins ◽  
Transcription Factor Complexes ◽  
Energy Sensing

Modification of mitochondrial content demands the synthesis of hundreds of proteins encoded by nuclear and mitochondrial genomes. The responsibility for coordination of this process falls to nuclear-encoded master regulators of transcription. DNA-binding proteins and coactivators integrate information from energy-sensing pathways and hormones to alter mitochondrial gene expression. In mammals, the signaling cascade for mitochondrial biogenesis can be described as follows: hormonal signals and energetic information are sensed by protein-modifying enzymes that in turn regulate the post-translational modification of transcription factors. Once activated, transcription-factor complexes form on promoter elements of many of the nuclear-encoded mitochondrial genes, recruiting proteins that remodel chromatin and initiate transcription. One master regulator in mammals, PGC-1α, is well studied because of its role in determining the metabolic phenotype of muscles, but also due to its importance in mitochondria-related metabolic diseases. However, relatively little is known about the role of this pathway in other vertebrates. These uncertainties raise broader questions about the evolutionary origins of the pathway and its role in generating the diversity in muscle metabolic phenotypes seen in nature.

scholarly journals Role of transcription factor-mediated nucleosome disassembly in PHO5 gene expression

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Hungyo Kharerin ◽  
Paike J. Bhat ◽  
John F. Marko ◽  
Ranjith Padinhateeri
Keyword(s):  
Gene Expression ◽  
Computational Study ◽  
Promoter Regions ◽  
Long Tail ◽  
Nucleosome Dynamics ◽  
Sequence Effects ◽  
Nucleosome Disassembly ◽  
Open Question ◽  
Kinetics Of

Abstract Studying nucleosome dynamics in promoter regions is crucial for understanding gene regulation. Nucleosomes regulate gene expression by sterically occluding transcription factors (TFs) and other non–histone proteins accessing genomic DNA. How the binding competition between nucleosomes and TFs leads to transcriptionally compatible promoter states is an open question. Here, we present a computational study of the nucleosome dynamics and organization in the promoter region of PHO5 gene in Saccharomyces cerevisiae. Introducing a model for nucleosome kinetics that takes into account ATP-dependent remodeling activity, DNA sequence effects and kinetics of TFs (Pho4p), we compute the probability of obtaining different “promoter states” having different nucleosome configurations. Comparing our results with experimental data, we argue that the presence of local remodeling activity (LRA) as opposed to basal remodeling activity (BRA) is crucial in determining transcriptionally active promoter states. By modulating the LRA and Pho4p binding rate, we obtain different mRNA distributions—Poisson, bimodal and long-tail. Through this work we explain many features of the PHO5 promoter such as sequence-dependent TF accessibility and the role of correlated dynamics between nucleosomes and TFs in opening/coverage of the TATA box. We also obtain possible ranges for TF binding rates and the magnitude of LRA.

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