Independent Losses of the Hypoxia-Inducible Factor (HIF) Pathway within Crustacea

2020 ◽  
Vol 37 (5) ◽  
pp. 1342-1349 ◽  
Author(s):  
Allie M Graham ◽  
Felipe S Barreto
Keyword(s):  
Cellular Response ◽  
Phylogenetic Analyses ◽  
Hypoxia Inducible Factor ◽  
Gene Families ◽  
Hypoxic Stress ◽  
Group Level ◽  
Low Oxygen ◽  
Transcriptomic Data ◽  
Cellular Oxygen ◽  
Hif Pathway

Abstract Metazoans respond to hypoxic stress via the hypoxia-inducible factor (HIF) pathway, a mechanism thought to be extremely conserved due to its importance in monitoring cellular oxygen levels and regulating responses to hypoxia. However, recent work revealed that key members of the HIF pathway have been lost in specific lineages (a tardigrade and a copepod), suggesting that this pathway is not as widespread in animals as previously assumed. Using genomic and transcriptomic data from 70 different species across 12 major crustacean groups, we assessed the degree to which the gene HIFα, the master regulator of the HIF pathway, was conserved. Mining of protein domains, followed by phylogenetic analyses of gene families, uncovered group-level losses of HIFα, including one across three orders within Cirripedia, and in three orders within Copepoda. For these groups, additional assessment showed losses of HIF repression machinery (EGLN and VHL). These results suggest the existence of alternative mechanisms for cellular response to low oxygen and highlight these taxa as models useful for probing these evolutionary outcomes.

scholarly journals Loss of the HIF pathway in a widely distributed intertidal crustacean, the copepodTigriopus californicus

2019 ◽  
Vol 116 (26) ◽  
pp. 12913-12918 ◽  
Author(s):  
Allie M. Graham ◽  
Felipe S. Barreto
Keyword(s):  
Oxygen Sensing ◽  
Phylogenetic Analyses ◽  
Hypoxia Inducible Factor ◽  
Small Animal ◽  
Gene Families ◽  
Regulatory Elements ◽  
Low Oxygen ◽  
Cellular Mechanisms ◽  
Genetic Components ◽  
Hif Pathway

Hypoxia is a major physiological constraint for which multicellular eukaryotes have evolved robust cellular mechanisms capable of addressing dynamic changes in O2availability. In animals, oxygen sensing and regulation is primarily performed by the hypoxia-inducible factor (HIF) pathway, and the key components of this pathway are thought to be highly conserved across metazoans. Marine intertidal habitats are dynamic environments, and their inhabitants are known to tolerate wide fluctuations in salinity, temperature, pH, and oxygen. In this study, we show that an abundant intertidal crustacean, the copepodTigriopus californicus, has lost major genetic components of the HIF pathway, but still shows robust survivorship and transcriptional response to hypoxia. Mining of protein domains across the genome, followed by phylogenetic analyses of gene families, did not identify two key regulatory elements of the metazoan hypoxia response, namely the transcription factorHIF-α and its oxygen-sensing prolyl hydroxylase repressor,EGLN. Despite this loss, phenotypic assays revealed that this species is tolerant to extremely low levels of available O2for at least 24 h at both larval and adult stages. RNA-sequencing (seq) of copepods exposed to nearly anoxic conditions showed differential expression of over 400 genes, with evidence for induction of glycolytic metabolism without a depression of oxidative phosphorylation. Moreover, genes involved in chitin metabolism and cuticle reorganization show categorically a consistent pattern of change during anoxia, highlighting this pathway as a potential solution to low oxygen availability in this small animal with no respiratory structures or pigment.

scholarly journals The last common ancestor of animals lacked the HIF pathway and respired in low-oxygen environments

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Daniel B Mills ◽  
Warren R Francis ◽  
Sergio Vargas ◽  
Morten Larsen ◽  
Coen PH Elemans ◽  
...  
Keyword(s):  
Common Ancestor ◽  
Hypoxia Inducible Factor ◽  
Last Common Ancestor ◽  
Low Oxygen ◽  
Oxygen Homeostasis ◽  
Animal Phyla ◽  
Cellular Oxygen ◽  
Hif Pathway ◽  
Anaerobic Production ◽  
Oxygen Concentrations

Animals have a carefully orchestrated relationship with oxygen. When exposed to low environmental oxygen concentrations, and during periods of increased energy expenditure, animals maintain cellular oxygen homeostasis by enhancing internal oxygen delivery, and by enabling the anaerobic production of ATP. These low-oxygen responses are thought to be controlled universally across animals by the hypoxia-inducible factor (HIF). We find, however, that sponge and ctenophore genomes lack key components of the HIF pathway. Since sponges and ctenophores are likely sister to all remaining animal phyla, the last common ancestor of extant animals likely lacked the HIF pathway as well. Laboratory experiments show that the marine sponge Tethya wilhelma maintains normal transcription under oxygen levels down to 0.25% of modern atmospheric saturation, the lowest levels we investigated, consistent with the predicted absence of HIF or any other HIF-like pathway. Thus, the last common ancestor of all living animals could have metabolized aerobically under very low environmental oxygen concentrations.

scholarly journals Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1213
Author(s):  
Peter Jianrui Liu ◽  
Peter Balfe ◽  
Jane A McKeating ◽  
Mirjam Schilling
Keyword(s):  
Oxygen Tension ◽  
Cellular Response ◽  
Viral Infections ◽  
Oxygen Sensing ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Pharmaceutical Agents ◽  
Hif Pathway ◽  
Essential Prerequisite

The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.

scholarly journals Variations within oxygen-regulated gene expression in humans

2009 ◽  
Vol 106 (1) ◽  
pp. 212-220 ◽  
Author(s):  
Jerome T. S. Brooks ◽  
Gareth P. Elvidge ◽  
Louisa Glenny ◽  
Jonathan M. Gleadle ◽  
Chun Liu ◽  
...  
Keyword(s):  
Cellular Response ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Hereditary Disease ◽  
Peripheral Blood Lymphocytes ◽  
Cellular Level ◽  
Normal Individuals ◽  
Regulated Gene Expression ◽  
Open Question ◽  
Hif Pathway

The effects of hypoxia on gene transcription are mainly mediated by a transcription factor complex termed hypoxia-inducible factor (HIF). Genetic manipulation of animals and studies of humans with rare hereditary disease have shown that modifying the HIF pathway affects systems-level physiological responses to hypoxia. It is, however, an open question whether variations in systems-level responses to hypoxia between individuals could arise from variations within the HIF system. This study sought to determine whether variations in the responsiveness of the HIF system at the cellular level could be detected between normal individuals. Peripheral blood lymphocytes (PBL) were isolated on three separate occasions from each of 10 healthy volunteers. After exposure of PBL to eight different oxygen tensions ranging from 20% to 0.1%, the expression levels of four HIF-regulated transcripts involved in different biological pathways were measured. The profile of expression of all four transcripts in PBL was related to oxygen tension in a curvilinear manner. Double logarithmic transformation of these data resulted in a linear relationship that allowed the response to be parameterized through a gradient and intercept. Analysis of variance (ANOVA) on these parameters showed that the level of between-subject variation in the gradients of the responses that was common across all four HIF-regulated transcripts was significant ( P = 0.008). We conclude that statistically significant variation within the cellular response to hypoxia can be detected between normal humans. The common nature of the variability across all four HIF-regulated genes suggests that the source of this variation resides within the HIF system itself.

scholarly journals Sequence and functional characterization of hypoxia-inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish, Fundulus heteroclitus

2017 ◽  
Vol 312 (3) ◽  
pp. R412-R425 ◽  
Author(s):  
Ian K. Townley ◽  
Sibel I. Karchner ◽  
Elena Skripnikova ◽  
Thomas E. Wiese ◽  
Mark E. Hahn ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Fundulus Heteroclitus ◽  
Phylogenetic Analyses ◽  
Functional Characterization ◽  
Hypoxia Inducible Factor ◽  
Estuarine Fish ◽  
Low Oxygen ◽  
Aryl Hydrocarbon ◽  
Transactivation Domains

The hypoxia-inducible factor (HIF) family of transcription factors plays central roles in the development, physiology, pathology, and environmental adaptation of animals. Because many aquatic habitats are characterized by episodes of low dissolved oxygen, fish represent ideal models to study the roles of HIF in the response to aquatic hypoxia. The estuarine fish Fundulus heteroclitus is found in habitats prone to hypoxia. It responds to low oxygen via behavioral, physiological, and molecular changes, and one member of the HIF family, HIF2α, has been previously described. Herein, cDNA sequencing, phylogenetic analyses, and genomic approaches were used to determine other members of the HIFα family from F. heteroclitus and their relationships to HIFα subunits from other vertebrates. In vitro and cellular approaches demonstrated that full-length forms of HIF1α, HIF2α, and HIF3α independently formed complexes with the β-subunit, aryl hydrocarbon receptor nuclear translocator, to bind to hypoxia response elements and activate reporter gene expression. Quantitative PCR showed that HIFα mRNA abundance varied among organs of normoxic fish in an isoform-specific fashion. Analysis of the F. heteroclitus genome revealed a locus encoding a second HIF2α—HIF2αb—a predicted protein lacking oxygen sensing and transactivation domains. Finally, sequence analyses demonstrated polymorphism in the coding sequence of each F. heteroclitus HIFα subunit, suggesting that genetic variation in these transcription factors may play a role in the variation in hypoxia responses among individuals or populations.

scholarly journals Hypoxia-Inducible Factor 1α Is Essential for Cell Cycle Arrest during Hypoxia

2003 ◽  
Vol 23 (1) ◽  
pp. 359-369 ◽  
Author(s):  
Nobuhito Goda ◽  
Heather E. Ryan ◽  
Bahram Khadivi ◽  
Wayne McNulty ◽  
Robert C. Rickert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Growth Arrest ◽  
Cell Types ◽  
Low Oxygen ◽  
Double Knockout ◽  
Cycle Arrest

ABSTRACT A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1α gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1α influenced p53, we also created double-knockout (HIF-1α null, p53 null) strains and cells. In both cell types, loss of HIF-1α abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1α genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1α causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1α-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1α dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.

scholarly journals Induction of the HIF pathway: Differential regulation by chemical hypoxia and oxygen glucose deprivation

2019 ◽  
Author(s):  
Alicia E. Novak ◽  
Susan M. Jones ◽  
J. Paul Elliott
Keyword(s):  
Transcriptional Activation ◽  
Cellular Response ◽  
Target Genes ◽  
Expression Patterns ◽  
Hypoxia Inducible Factor ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Oxygen Levels ◽  
Chemical Hypoxia ◽  
Hif Pathway

AbstractThe Hypoxia Inducible Factor (HIF) proteins are the master regulators in the cellular response to varying oxygen levels, including hypoxia. The HIF complex is stabilized and accumulates when oxygen levels drop through inhibition of a degradative enzyme. An active HIF complex can act as a transcriptional regulator of hundreds of genes. In turn, these genes determine the response of the cell by inducing pathways which can promote survival, or result in cell death. However, little is known about the regulation of the transcriptional process. We were interested in learning more about the time dependence of transcriptional activation in order to target those pathways which could enhance cell survival after ischemia. Using mouse hippocampal organotypic cultures (HOTCs), we compared oxygen-glucose deprivation with the hypoxia mimetic cobalt, which inhibits the oxygen dependent prolyl hydroylase and blocks degradation of the HIF proteins. We demonstrated that two of the most studied HIF target genes (VEGF, EPO) as well as HIF structural genes show complex time and dose-dependent expression patterns in response to the two different insults. Understanding of these molecular responses is crucial for the development of future treatments to enhance recovery from hypoxia and stroke.

scholarly journals HIF Pathways in Clear Cell Renal Cancer

2021 ◽  
Author(s):  
Olivia Lombardi ◽  
David Robert Mole
Keyword(s):  
Cell Proliferation ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Von Hippel Lindau ◽  
Pathway Activation ◽  
Cellular Energetics ◽  
Cellular Oxygen ◽  
Immune Destruction ◽  
Hif Pathway ◽  
Cell Renal Cancer

Clear cell renal cancers (ccRCC) are characterized by inactivation of the VHL (von Hippel–Lindau) tumor suppressor. Work leading to the 2019 Nobel Prize for Physiology or Medicine has shown that this is central to cellular oxygen-sensing, orchestrated by the HIF (hypoxia-inducible factor) transcription factors. These regulate hundreds of genes that underpin many hallmarks of cancer, including angiogenesis, cellular energetics, cell proliferation, resisting cell death, and avoiding immune destruction. However, HIF also promotes processes that are detrimental to cancer cells. Therefore, the overall consequence of HIF pathway activation is a balance of these influences. We explore how variations in the HIF pathway during tumorigenesis alter this balance to promote ccRCC formation.

scholarly journals Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2340
Author(s):  
Mykyta I. Malkov ◽  
Chee Teik Lee ◽  
Cormac T. Taylor
Keyword(s):  
Inflammatory Cytokines ◽  
Cellular Response ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Wide Range ◽  
Inflammatory Stimuli ◽  
Factor Α ◽  
Hif Pathway ◽  
The Impact ◽  
Pro Inflammatory Cytokines

Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.

scholarly journals Differential Responsiveness in VEGF Receptor Subtypes to Hypoxic Stress in Various Tissues of Plateau Animals

2017 ◽  
pp. 357-362 ◽  
Author(s):  
H.-C. XIE ◽  
J.-G. LI ◽  
J.-P. HE
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Receptor Subtypes ◽  
Vegf Receptor ◽  
Hypoxic Stress ◽  
Adaptive Responses ◽  
Sprague Dawley ◽  
Low Oxygen ◽  
Hypoxic Environment

With hypoxic stress, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) are elevated and their responses are altered in skeletal muscles of plateau animals [China Qinghai-Tibetan plateau pikas (Ochotona curzoniae)] as compared with control animals [normal lowland Sprague-Dawley (SD) rats]. The results indicate that HIF-1α and VEGF are engaged in physiological functions under hypoxic environment. The purpose of the current study was to examine the protein levels of VEGF receptor subtypes (VEGFRs: VEGFR-1, VEGFR-2 and VEGFR-3) in the end organs, namely skeletal muscle, heart and lung in response to hypoxic stress. ELISA and Western blot analysis were employed to determine HIF-1α and the protein expression of VEGFRs in control animals and plateau pikas. We further blocked HIF-1α signal to determine if HIF-1α regulates alternations in VEGFRs in those tissues. We hypothesized that responsiveness of VEGFRs in the major end organs of plateau animals is differential with insult of hypoxic stress and is modulated by low oxygen sensitive HIF-1α. Our results show that hypoxic stress induced by exposure of lower O2 for 6 h significantly increased the levels of VEGFR-2 in skeletal muscle, heart and lung and the increases were amplified in plateau pikas. Our results also demonstrate that hypoxic stress enhanced VEGFR-3 in lungs of plateau animals. Nonetheless, no significant alternations in VEGFR-1 were observed in those tissues with hypoxic stress. Moreover, we observed decreases of VEGFR-2 in skeletal muscle, heart and lung; and decreases of VEGFR-3 in lung following HIF-1α inhibition. Overall, our findings suggest that in plateau animals 1) responsiveness of VEGFRs is different under hypoxic environment; 2) amplified VEGFR-2 response appears in skeletal muscle, heart and lung, and enhanced VEGFR-3 response is mainly observed in lung; 3) HIF-1α plays a regulatory role in the levels of VEGFRs. Our results provide the underlying cellular and molecular mechanisms responsible for hypoxic environment in plateau animals, having an impact on research of physiological and ecological adaptive responses to acute or chronic hypoxic stress in humans who living at high attitude and who live at a normal sea level but suffer from hypoxic disorders.

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