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

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.

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Author response: The last common ancestor of animals lacked the HIF pathway and respired in low-oxygen environments

10.7554/elife.31176.024 ◽

2017 ◽

Author(s):

Daniel B Mills ◽

Warren R Francis ◽

Sergio Vargas ◽

Morten Larsen ◽

Coen PH Elemans ◽

...

Keyword(s):

Common Ancestor ◽

Author Response ◽

Last Common Ancestor ◽

Low Oxygen ◽

Hif Pathway

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Decision letter: The last common ancestor of animals lacked the HIF pathway and respired in low-oxygen environments

10.7554/elife.31176.023 ◽

2017 ◽

Keyword(s):

Common Ancestor ◽

Last Common Ancestor ◽

Low Oxygen ◽

Hif Pathway

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

Molecular Biology and Evolution ◽

10.1093/molbev/msaa008 ◽

2020 ◽

Vol 37 (5) ◽

pp. 1342-1349 ◽

Cited By ~ 1

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.

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Ancient Atmospheres and the Evolution of Oxygen Sensing Via the Hypoxia-Inducible Factor in Metazoans

Physiology ◽

10.1152/physiol.00029.2010 ◽

2010 ◽

Vol 25 (5) ◽

pp. 272-279 ◽

Cited By ~ 68

Author(s):

Cormac T. Taylor ◽

Jennifer C. McElwain

Keyword(s):

Oxygen Sensing ◽

Atmospheric Oxygen ◽

Hypoxia Inducible Factor ◽

Transcriptional Response ◽

Oxygen Levels ◽

Selection Force ◽

Cellular Oxygen ◽

Hif Pathway ◽

Evolution Of Oxygen ◽

Oxygen Concentrations

Metazoan diversification occurred during a time when atmospheric oxygen levels fluctuated between 15 and 30%. The hypoxia-inducible factor (HIF) is a primary regulator of the adaptive transcriptional response to hypoxia. Although the HIF pathway is highly conserved, its complexity increased during periods when atmospheric oxygen concentrations were increasing. Thus atmospheric oxygen levels may have provided a selection force on the development of cellular oxygen-sensing pathways.

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Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans

10.1101/2021.03.12.435071 ◽

2021 ◽

Author(s):

Dingxia Feng ◽

Zhiwei Zhai ◽

Zhiyong Shao ◽

Yi Zhang ◽

Jo Anne Powell-Coffman

Keyword(s):

Oxidative Stress ◽

Hypoxia Inducible Factor ◽

Regulatory Sequences ◽

Low Oxygen ◽

Transcriptional Responses ◽

C Elegans ◽

Protein Levels ◽

Oxygen Homeostasis ◽

Genome Wide ◽

A Genome

AbstractDuring development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57:GFP in C. elegans. Interestingly, only a subset of these effects requires hif-1. Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57:GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat, increases expression of a Pegl-9:GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.

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HIF Pathways in Clear Cell Renal Cancer

10.5772/intechopen.96539 ◽

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.

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The last common ancestor of most bilaterian animals possessed at least 9 opsins

10.1101/052902 ◽

2016 ◽

Cited By ~ 1

Author(s):

MD Ramirez ◽

AN Pairett ◽

MS Pankey ◽

JM Serb ◽

DI Speiser ◽

...

Keyword(s):

Gene Family ◽

Complex Traits ◽

Common Ancestor ◽

Opsin Gene ◽

Last Common Ancestor ◽

Phylogenetic Information ◽

Animal Evolution ◽

Animal Phyla ◽

Evolution Understanding

AbstractThe opsin gene family encodes key proteins animals use to sense light and has expanded dramatically since it originated early in animal evolution. Understanding the origins of opsin diversity can offer clues to how separate lineages of animals have repurposed different opsin paralogs for different light-detecting functions. However, the more we look for opsins outside of eyes and from additional animal phyla, the more opsins we uncover, suggesting we still do not know the true extent of opsin diversity, nor the ancestry of opsin diversity in animals. To estimate the number of opsin paralogs present in both the last common ancestor of the Nephrozoa (bilaterians excluding Xenoacoelomorpha), and the ancestor of Cnidaria + Bilateria, we reconstructed a reconciled opsin phylogeny using sequences from 14 animal phyla, especially the traditionally poorly-sampled echinoderms and molluscs. Our analysis strongly supports a repertoire of at least nine opsin paralogs in the bilaterian ancestor and at least four opsin paralogs in the last common ancestor of Cnidaria + Bilateria. Thus, the kernels of extant opsin diversity arose much earlier in animal history than previously known. Further, opsins likely duplicated and were lost many times, with different lineages of animals maintaining different repertoires of opsin paralogs. This phylogenetic information can inform hypotheses about the functions of different opsin paralogs and be used to understand how and when opsins were incorporated into complex traits like eyes and extraocular sensors.

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The von Hippel Lindau/Hypoxia-inducible Factor (HIF) Pathway Regulates the Transcription of the HIF-Proline Hydroxylase Genes in Response to Low Oxygen

Journal of Biological Chemistry ◽

10.1074/jbc.m308862200 ◽

2003 ◽

Vol 278 (49) ◽

pp. 48690-48695 ◽

Cited By ~ 120

Author(s):

Luis del Peso ◽

María C. Castellanos ◽

Elisa Temes ◽

Silvia Martín-Puig ◽

Yolanda Cuevas ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Low Oxygen ◽

Von Hippel Lindau ◽

Hif Pathway ◽

Proline Hydroxylase

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Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

Cells ◽

10.3390/cells8020155 ◽

2019 ◽

Vol 8 (2) ◽

pp. 155 ◽

Cited By ~ 11

Author(s):

Ben Wielockx ◽

Tatyana Grinenko ◽

Peter Mirtschink ◽

Triantafyllos Chavakis

Keyword(s):

Cell Fate ◽

Current Knowledge ◽

Hypoxia Inducible Factor ◽

Adult Life ◽

Low Oxygen ◽

Hematopoietic Stem ◽

Metabolism Regulation ◽

Hsc Niche ◽

Hif Pathway ◽

The Impact

The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis.

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Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis

Viruses ◽

10.3390/v12111213 ◽

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.

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