A systematic study of HIF1A cofactors in hypoxic cancer cells

Abstract

Hypoxia inducible factor 1 alpha (HIF1A) is a transcription factor (TF) that forms highly structural and functional protein-protein interactions with other TFs to promote gene expression in hypoxic cancer cells. However, despite the importance of these TF-TF interactions, we still lack a comprehensive view of many of the TF cofactors involved and how they cooperate. In this study, we systematically studied HIF1A cofactors in eight cancer cell lines using the computational motif mining tool, SIOMICS, and discovered 201 potential HIF1A cofactors, which included 21 of the 29 known HIF1A cofactors in public databases. These 201 cofactors were statistically and biologically significant, with 19 of the top 37 cofactors in our study directly validated in the literature. The remaining 18 were novel cofactors. These discovered cofactors can be essential to HIF1A's regulatory functions and may lead to the discovery of new therapeutic targets in cancer treatment.

Figure 1

The pipeline to study hypoxia motifs and cofactor pairs.

Figure 2

The predicted cofactors are biologically sound. (A) and (B) Overrepresentation of the known TF-TF interactions in the predicted cofactor pairs. One predicted motif may correspond to multiple TFs in (A) while only one TF in (B). (C) The top 37 HIF1A cofactors ranked by the multiple of the -log of the STAMP E-value of its predicted motif and the number of motif modules in which this predicted motif occurred. An orange bar indicates that these cofactors were in BIND, HPRD, or BioGRID. A green bar indicates that they were not in the above databases but supported by literature. A blue bar indicates the remaining novel cofactors.

Figure 3

The distance of the HIF1A ChIP-seq peak regions to the proximal genes. Using the ChIPseeker tool, the HIF1A peaks were visualized in terms of their proximity to nearby genes.

Figure 4

Interactions between discovered HIF1A cofactors. (A) Cytoscape representation of the top 37 TFs and their interactions with one another. (B) Cytoscape network of interactions between six top novel TF cofactors, HSF1, E2F4, E2F6, STAT1, FOSL2, NRF1, and KLF4. SIOMICS predicted the edges shown.