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Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature

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Tumor Biology

Abstract

Hypoxia-inducible factor-1α (HIF-1α) has crucial role in adapting cells to hypoxia through expression regulation of many genes. Identification of HIF-1α target genes (HIF-1α-TGs) is important for understanding the adapting mechanism. The aim of the present study was to collect known HIF-1α-TGs and identify their associated pathways. Targets and associated genomics data were retrieved using PubMed, WoS (http://apps.webofknowledge.com/), HGNC (http://www.genenames.org/), NCBI (http://www.ncbi.nlm.nih.gov/), Ensemblv.84 (http://www.ensembl.org/index.html), DAVID Bioinformatics Resources (https://david.ncifcrf.gov/), and Disease Ontology database (http://disease-ontology.org/). From 51 papers, we collected 98 HIF-1α TGs found to be associated with 20 pathways, including metabolism of carbohydrates and pathways in cancer. Reanalysis of genomic coordinates of published HREs (hypoxia response elements) revealed six polymorphisms within HRE sites (HRE-SNPs): ABCG2, ACE, CA9, and CP. Due to large heterogeneity of results presentation in scientific literature, we also propose a first step towards reporting standardization of HIF-1α-target interactions consisting of ten relevant data types. Suggested minimal checklist for reporting will enable faster development of a complete catalog of HIF-1α-TGs, data sharing, bioinformatics analyses, and setting novel more targeted hypotheses. The proposed format for data standardization is not yet complete but presents a baseline for further optimization of the protocol with additional details, for example, regarding the experimental validation.

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Correspondence to Tanja Kunej.

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This work was supported by the Slovenian Research Agency (ARRS) through the Research program (P4-0220).

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Supplemental Figure 1

. Identified polymorphisms within HRE sites of four target genes. Sequence of the target genes: ABCG2 (A), ACE (B), CA9 (C), and CP (D). Biotype of identified polymorphisms within HRE sites (E). (DOCX 1512 kb)

Supplemental Table 1

. Collected data associated with 98 HIF-1α target genes. (XLSX 38 kb)

Supplemental Table 2

. Pathway analysis of HIF-1α downstream targets. (DOCX 17 kb)

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Slemc, L., Kunej, T. Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature. Tumor Biol. 37, 14851–14861 (2016). https://doi.org/10.1007/s13277-016-5331-4

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