Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health.

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Roles Of HIF and 2-Oxoglutarate Dependent Enzymes in Controlling Gene Expression In Hypoxia

10.20944/preprints202011.0651.v1 ◽

2020 ◽

Author(s):

Julianty Frost ◽

Mark Frost ◽

Michael Batie ◽

Hao Jiang ◽

Sonia Rocha

Keyword(s):

Gene Expression ◽

Hypoxia Inducible Factor ◽

Transcriptional Regulator ◽

Hydroxylase Activity ◽

Control Of Gene Expression ◽

Prolyl Hydroxylases ◽

Chromatin Organisation ◽

Sense And Respond ◽

Almost All ◽

And Function

Hypoxia — reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OG dioxyenases in the control of gene expression in response to hypoxia and their relevance to human cancers.

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Combinatorial Control of Gene Expression

BioMed Research International ◽

10.1155/2013/407263 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 18

Author(s):

Soumya Bhattacharjee ◽

Kaushik Renganaath ◽

Rajesh Mehrotra ◽

Sandhya Mehrotra

Keyword(s):

Gene Expression ◽

Short Description ◽

Controlling Factors ◽

Environmental Cues ◽

Control Of Gene Expression ◽

Environmental Signals ◽

Combinatorial Control ◽

Sense And Respond ◽

Eukaryotic Organisms

The complexity and diversity of eukaryotic organisms are a feat of nature’s engineering. Pulling the strings of such an intricate machinery requires an even more masterful and crafty approach. Only the number and type of responses that they generate exceed the staggering proportions of environmental signals perceived and processed by eukaryotes. Hence, at first glance, the cell’s sparse stockpile of controlling factors does not seem remotely adequate to carry out this response. The question as to how eukaryotes sense and respond to environmental cues has no single answer. It is an amalgamation, an interplay between several processes, pathways, and factors—a combinatorial control. A short description of some of the most important elements that operate this entire conglomerate is given in this paper.

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Molecular Assessment of Epiretinal Membrane: Activated Microglia, Oxidative Stress and Inflammation

Antioxidants ◽

10.3390/antiox9080654 ◽

2020 ◽

Vol 9 (8) ◽

pp. 654 ◽

Cited By ~ 1

Author(s):

Sushma Vishwakarma ◽

Rishikesh Kumar Gupta ◽

Saumya Jakati ◽

Mudit Tyagi ◽

Rajeev Reddy Pappuru ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Epiretinal Membrane ◽

Hypoxia Inducible Factor ◽

Gene Expression Signature ◽

Cell Types ◽

Activated Microglia ◽

Inflammatory Conditions ◽

New Information ◽

And Function

Fibrocellular membrane or epiretinal membrane (ERM) forms on the surface of the inner limiting membrane (ILM) in the inner retina and alters the structure and function of the retina. ERM formation is frequently observed in ocular inflammatory conditions, such as proliferative diabetic retinopathy (PDR) and retinal detachment (RD). Although peeling of the ERM is used as a surgical intervention, it can inadvertently distort the retina. Our goal is to design alternative strategies to tackle ERMs. As a first step, we sought to determine the composition of the ERMs by identifying the constituent cell-types and gene expression signature in patient samples. Using ultrastructural microscopy and immunofluorescence analyses, we found activated microglia, astrocytes, and Müller glia in the ERMs from PDR and RD patients. Moreover, oxidative stress and inflammation associated gene expression was significantly higher in the RD and PDR membranes as compared to the macular hole samples, which are not associated with inflammation. We specifically detected differential expression of hypoxia inducible factor 1-α (HIF1-α), proinflammatory cytokines, and Notch, Wnt, and ERK signaling pathway-associated genes in the RD and PDR samples. Taken together, our results provide new information to potentially develop methods to tackle ERM formation.

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Critical Role of Types 2 and 3 Deiodinases in the Negative Regulation of Gene Expression by T3 in the Mouse Cerebral Cortex

Endocrinology ◽

10.1210/en.2011-1905 ◽

2012 ◽

Vol 153 (6) ◽

pp. 2919-2928 ◽

Cited By ~ 47

Author(s):

Arturo Hernandez ◽

Beatriz Morte ◽

Mónica M. Belinchón ◽

Ainhoa Ceballos ◽

Juan Bernal

Keyword(s):

Gene Expression ◽

Cerebral Cortex ◽

Thyroid Hormone ◽

Critical Role ◽

Regulation Of Gene Expression ◽

Control Of Gene Expression ◽

High Doses ◽

And Function ◽

Type 3

Thyroid hormones regulate brain development and function through the control of gene expression, mediated by binding of T3 to nuclear receptors. Brain T3 concentration is tightly controlled by homeostatic mechanisms regulating transport and metabolism of T4 and T3. We have examined the role of the inactivating enzyme type 3 deiodinase (D3) in the regulation of 43 thyroid hormone-dependent genes in the cerebral cortex of 30-d-old mice. D3 inactivation increased slightly the expression of two of 22 positively regulated genes and significantly decreased the expression of seven of 21 negatively regulated genes. Administration of high doses of T3 led to significant changes in the expression of 12 positive genes and three negative genes in wild-type mice. The response to T3 treatment was enhanced in D3-deficient mice, both in the number of genes and in the amplitude of the response, demonstrating the role of D3 in modulating T3 action. Comparison of the effects on gene expression observed in D3 deficiency with those in hypothyroidism, hyperthyroidism, and type 2 deiodinase (D2) deficiency revealed that the negative genes are more sensitive to D2 and D3 deficiencies than the positive genes. This observation indicates that, in normal physiological conditions, D2 and D3 play critical roles in maintaining local T3 concentrations within a very narrow range. It also suggests that negatively and positively regulated genes do not have the same physiological significance or that their regulation by thyroid hormone obeys different paradigms at the molecular or cellular levels.

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Expression of psbA1 gene in Synechocystis sp. PCC 6803 is influenced by CO2

Open Life Sciences ◽

10.1515/biol-2017-0018 ◽

2017 ◽

Vol 12 (1) ◽

pp. 156-161

Author(s):

Ciprian Chiş ◽

Dalton Carmel ◽

luliana Chiş ◽

Aurel Ardelean ◽

Nicolae Dragos ◽

...

Keyword(s):

Gene Expression ◽

Photosystem Ii ◽

Inorganic Carbon ◽

Microaerobic Conditions ◽

Almost All ◽

And Function ◽

First Time ◽

Encoding Genes ◽

Synechocystis Sp ◽

Pcc 6803

AbstractIn almost all cyanobacteria a small gene family encodes the photosystem II reaction center D1 proteins that play vital roles in the cell. Recently, several types of this protein were functionally characterised and the conditions for their transcript regulation were identified. One of the D1-encoding genes previously believed to be silent is induced by microaerobic conditions. This gene was first described in Synechocystis sp. PCC 6803 as psbA1 encoding the D1 isoform. When Synechocystis cells are shifted from high to ambient level CO2 we recorded an increase in gene expression, similar, but to a lesser extent, to microaerobic conditions. When synthetic air is used to remove the ambient CO2, the induction of the gene is absent. We documented for the first time that expression of a psbA gene is regulated by the inorganic carbon status of the cell. Our conclusion is that both CO2 and microaerobic conditions are independently influencing the expression of psbA1 gene in Synechocystis sp. PCC 6803. Hence, it is crucial to understand the mechanisms of regulation and function of D1 proteins as it could be used for future bio-technological applications as a virtual tool-box for modulating the function of PSII.

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Genome-Wide Gene Expression in relation to Age in Large Laboratory Cohorts of Drosophila melanogaster

Genetics Research International ◽

10.1155/2015/835624 ◽

2015 ◽

Vol 2015 ◽

pp. 1-19 ◽

Cited By ~ 12

Author(s):

Kimberly A. Carlson ◽

Kylee Gardner ◽

Anjeza Pashaj ◽

Darby J. Carlson ◽

Fang Yu ◽

...

Keyword(s):

Gene Expression ◽

Drosophila Melanogaster ◽

Immune Function ◽

Expression Patterns ◽

Self Organizing Map ◽

Control Of Gene Expression ◽

Genome Wide ◽

Complex Process ◽

Temporal Variance ◽

And Function

Aging is a complex process characterized by a steady decline in an organism’s ability to perform life-sustaining tasks. In the present study, two cages of approximately 12,000 mated Drosophila melanogaster females were used as a source of RNA from individuals sampled frequently as a function of age. A linear model for microarray data method was used for the microarray analysis to adjust for the box effect; it identified 1,581 candidate aging genes. Cluster analyses using a self-organizing map algorithm on the 1,581 significant genes identified gene expression patterns across different ages. Genes involved in immune system function and regulation, chorion assembly and function, and metabolism were all significantly differentially expressed as a function of age. The temporal pattern of data indicated that gene expression related to aging is affected relatively early in life span. In addition, the temporal variance in gene expression in immune function genes was compared to a random set of genes. There was an increase in the variance of gene expression within each cohort, which was not observed in the set of random genes. This observation is compatible with the hypothesis that D. melanogaster immune function genes lose control of gene expression as flies age.

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Oxygen-dependent gene expression in fishes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00626.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. R1079-R1090 ◽

Cited By ~ 149

Author(s):

Mikko Nikinmaa ◽

Bernard B. Rees

Keyword(s):

Gene Expression ◽

Mammalian Cells ◽

Hypoxia Inducible Factor ◽

Transcriptional Response ◽

Hypoxia Tolerance ◽

Hypoxic Exposure ◽

Low Oxygen ◽

Mammalian Development ◽

Molecular Responses ◽

And Function

The role of oxygen in regulating patterns of gene expression in mammalian development, physiology, and pathology has received increasing attention, especially after the discovery of the hypoxia-inducible factor (HIF), a transcription factor that has been likened to a “master switch” in the transcriptional response of mammalian cells and tissues to low oxygen. At present, considerably less is known about the molecular responses of nonmammalian vertebrates and invertebrates to hypoxic exposure. Because many animals live in aquatic habitats that are variable in oxygen tension, it is relevant to study oxygen-dependent gene expression in these animals. The purpose of this review is to discuss hypoxia-induced gene expression in fishes from an evolutionary and ecological context. Recent studies have described homologs of HIF in fish and have begun to evaluate their function. A number of physiological processes are known to be altered by hypoxic exposure of fish, although the evidence linking them to HIF is less well developed. The diversity of fish presents many opportunities to evaluate if inter- and intraspecific variation in HIF structure and function correlate with hypoxia tolerance. Furthermore, as an aquatic group, fish offer the opportunity to examine the interactions between hypoxia and other stressors, including pollutants, common in aquatic environments. It is possible, if not likely, that results obtained by studying the molecular responses of fish to hypoxia will find parallels in the oxygen-dependent responses of mammals, including humans. Moreover, novel responses to hypoxia could be discovered through studies of this diverse and species-rich group.

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De novo Design of Translational RNA Repressors

10.1101/501767 ◽

2018 ◽

Cited By ~ 4

Author(s):

Paul D. Carlson ◽

Cameron J. Glasscock ◽

Julius B. Lucks

Keyword(s):

Gene Expression ◽

Synthetic Biology ◽

De Novo ◽

Genetic Circuit ◽

Bacterial Cells ◽

Control Of Gene Expression ◽

Sequence Characterization ◽

Mrna Targets ◽

Modern Drug ◽

And Function

ABSTRACTA central goal of synthetic biology is the development of methods for the predictable control of gene expression. RNA is an attractive substrate by which to achieve this goal because the relationship between its sequence, structure, and function is being uncovered with increasing depth. In addition, design approaches that use this relationship are becoming increasingly effective, as evidenced by significant progress in the de novo design of RNA-based gene regulatory mechanisms that activate transcription and translation in bacterial cells. However, the design of synthetic RNA mechanisms that are efficient and versatile repressors of gene expression has lagged, despite their importance for gene regulation and genetic circuit construction. We address this gap by developing two new classes of RNA regulators, toehold repressors and looped antisense oligonucleotides (LASOs), that repress translation of a downstream gene in response to an arbitrary input RNA sequence. Characterization studies show that these designed RNAs robustly repress translation, are highly orthogonal, and can be multiplexed with translational activators. We show that our LASO design can repress endogenous mRNA targets and distinguish between closely-related genes with a high degree of specificity and predictability. These results demonstrate significant yet easy-to-implement improvements in the design of synthetic RNA repressors for synthetic biology, and point more broadly to design principles for repressive RNA interactions relevant to modern drug design.

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Analysis of Structure and function by the LysR-Type Transcriptional Regulator CbbR of Nostoc sp. PCC 7120

10.1101/2020.08.04.235895 ◽

2020 ◽

Author(s):

Hao-Xi Xu ◽

Shu-Jing Han ◽

Yong-Liang Jiang ◽

Cong-Zhao Zhou

Keyword(s):

Gene Expression ◽

Crystal Structure ◽

Carbon Metabolism ◽

Transcriptional Regulator ◽

Structure And Function ◽

Protein Crystals ◽

Expression And Purification ◽

Key Enzyme ◽

And Function ◽

Pcc 7120

ABSTRACTThe LysR-type Calvin–Benson–Bassham cycle transcriptional regulator CbbR plays an important role in CO2 fixation in carbon metabolism in nature, which regulates the gene expression of the key enzyme RibisCO in the Calvin–Benson–Bassham (CBB) cycle. In this study, we optimized the conditions for the transformation, expression, and purification of CbbR in the model algae Nostoc sp. PCC 7120, obtained nick-DNA fragments that could tightly bind to CbbR_7120, and finally obtained CbbR protein crystals. These findings provide great assistance for the final crystallization of CbbR to solve the crystal structure of CbbR, and lay the foundation for understanding the mechanism of CO2 fixation in the CBB cycle.

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Role of Thyroid Hormone Receptor Subtypes α and β on Gene Expression in the Cerebral Cortex and Striatum of Postnatal Mice

Endocrinology ◽

10.1210/en.2012-2189 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1940-1947 ◽

Cited By ~ 23

Author(s):

Pilar Gil-Ibañez ◽

Beatriz Morte ◽

Juan Bernal

Keyword(s):

Gene Expression ◽

Cerebral Cortex ◽

Thyroid Hormone Receptor ◽

Intrinsic Activity ◽

Receptor Subtypes ◽

Rt Pcr ◽

Control Of Gene Expression ◽

Total Absence ◽

And Function

Abstract The effects of thyroid hormones (THs) on brain development and function are largely mediated by the control of gene expression. This is achieved by the binding of the genomically active T3 to transcriptionally active nuclear TH receptors (TRs). T3 and the TRs can either induce or repress transcription. In hypothyroidism, the reduction of T3 lowers the expression of a set of genes, the positively regulated genes, and increases the expression of negatively regulated genes. Two mechanisms may account for the effect of hypothyroidism on genes regulated directly by T3: first, the loss of T3 signaling and TR transactivation, and second, an intrinsic activity of the unliganded TRs directly responsible for repression of positive genes and enhancement of negative genes. To analyze the contribution of the TR subtypes α and β, we have measured by RT-PCR the expression of a set of positive and negative genes in the cerebral cortex and the striatum of TR-knockout male and female mice. The results indicate that TRα1 exerts a predominant but not exclusive role in the regulation of positive and negative genes. However, a fraction of the genes analyzed are not or only mildly affected by the total absence of TRs. Furthermore, hypothyroidism has a mild effect on these genes in the absence of TRα1, in agreement with a role of unliganded TRα1 in the effects of hypothyroidism.

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