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.
Highlights
The maintenance of oxygen homeostasis is a critical biological constraint that requires coordinated regulation of a variety of genes, especially for metazoans whom rely mostly on aerobic energy production [1,2]
Hypoxia inducible factors (HIF) genes are part of the larger basic helix-loophelix (bHLH)+PAS gene family, and we initially identified all proteins in each genome that contained a bHLH DNA binding domain plus either one or two PAS domains
It is possible that the HMMR model did not recognize specific protein sequences due to significant divergence of the bHLH domain in the genomes searched; the Pfam bHLH model is based on an alignment of 13,830 sequences using 1,653 species across eukaryotes, suggesting it is a robust domain sequence model
Summary
The maintenance of oxygen homeostasis is a critical biological constraint that requires coordinated regulation of a variety of genes, especially for metazoans whom rely mostly on aerobic energy production [1,2]. During periods of reduced oxygen supply, the most profound changes in gene expression are mediated by transcription factors known as Hypoxia inducible factors (HIF) [4]. The HIF transcription factor family plays a crucial role in cellular response to low oxygen tension in a variety of organisms, and is frequently. HIF transcription factor evolution in eukaryotes associated with adaptations to high altitude [5,6,7,8,9,10,11,12] and other oxygen limited environments [13]. Members of the HIF family are known for their roles in vasodilation, cell migration, signaling, and cell fate specification [17]
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