Hypoxia Inducible Factor (HIF) transcription factor family expansion, diversification, divergence and selection in eukaryotes

Abstract

Hypoxia inducible factor (HIF) transcription factors are crucial for regulating a variety of cellular activities in response to oxygen stress (hypoxia). In this study, we determine the evolutionary history of HIF genes and their associated transactivation domains, as well as perform selection and functional divergence analyses across their four characteristic domains. Here we show that the HIF genes are restricted to metazoans: At least one HIF-α homolog is found within the genomes of non-bilaterians and bilaterian invertebrates, while most vertebrate genomes contain between two and six HIF-α genes. We also find widespread purifying selection across all four characteristic domain types, bHLH, PAS, NTAD, CTAD, in HIF-α genes, and evidence for Type I functional divergence between HIF-1α, HIF-2α /EPAS, and invertebrate HIF genes. Overall, we describe the evolutionary histories of the HIF transcription factor gene family and its associated transactivation domains in eukaryotes. We show that the NTAD and CTAD domains appear de novo, without any appearance outside of the HIF-α subunits. Although they both appear in invertebrates as well as vertebrate HIF- α sequences, there seems to have been a substantial loss across invertebrates or were convergently acquired in these few lineages. We reaffirm that HIF-1α is phylogenetically conserved among most metazoans, whereas HIF-2α appeared later. Overall, our findings can be attributed to the substantial integration of this transcription factor family into the critical tasks associated with maintenance of oxygen homeostasis and vascularization, particularly in the vertebrate lineage.

Iron metabolic pathways in the processes of sponge plasticity

“…The outer mitochondrial membrane iron-sulfur protein Mito-NEET controls intramitochondrial iron concentrations and allows tumor cells to tolerate reactive oxygen species and to avoid ferroptosis via activation of the PI3K/Akt/mTOR and COX2/ AKT/ERK1/2 pathways [12,14,15]. At low oxygen availability, the hypoxia-inducible factors (HIFs) regulate the expression of genes that mediate cell's adaptive responses connected to mitochondrial function, energy metabolism, oxygen binding and delivery [2,[16][17][18][19]. The response to hypoxia and the ability to regulate oxygen requirements have been developed in the ancestral animals and intrinsically linked to the metabolism of iron and sulfur [20,21].…”

Refined control of cell stemness allowed animal evolution in the oxic realm

“…Our HIFresults generally agree with previous findings, such as the lack of HIF-α expression in sponges 6 and ctenophora 5 . Our analysis of the cnidarian Hydra vulgaris, lacking the c-terminal oxygen sensing domain of its HIF-like protein, however differs from how the other cnidarian Nematostella vectensis has been shown in three studies to express a HIF 3,5,6 . A loss of data, such as poor recovery or alignment of the Hydra vulgaris proteome, is more likely than a faulty gain of data.…”

“…oxic conditions (>1-3%) promote cell differentiation 5 . Here, we evaluate an evolution of cell stemness control 30 in animals and discuss how the model maps onto geological and biological evidence of stemness and the 31 varying capacities of animals to live in the oxic realm.…”

Cancer research encourages explorations of hypoxic conditions as a necessity for multicellularity and how animals solved the challenge of life in the oxic setting

“…All modern bilateral animals possess HIFs [9][10][11]. HIF-2 α is exclusive to vertebrates and EPO appear first in the genomes of fish [7].…”