ZBTB2 is Recruited to a Specific Subset of HIF-1 Target Loci to Facilitate Full Gene Expression Under Hypoxia

[Display omitted] •HIF-1 can bind to its consensus binding sequence and recruit ZBTB2 to a subset of target gene loci.•ZBTB2 recruitment causes an increase in p300-mediated histone acetylation and ultimately leads to full expression of a subset of HIF-1 target genes under hypoxia.•HIF-1 target gene expression under hypoxia requires factors other than HIF-1, and identify ZBTB2 as a novel coactivator contributing to the process. The cellular response to hypoxia is mainly governed by a transcription factor, hypoxia-inducible factor 1 (HIF-1). Although upregulation of HIF-1 target genes has been hypothesized to require interaction of HIF-1 with other coactivators, much remains to be elucidated regarding the underlying mechanisms. Here, we demonstrate that zinc finger and BTB domain-containing protein 2 (ZBTB2) enhances the expression of certain HIF-1 target genes under hypoxia. ChIP-Seq analysis showed that there is a subset of HIF-1 target genes with overlapping HIF-1 and ZBTB2 peaks. Examination of a representative gene, EGFR antisense RNA 1 (EGFR-AS1), showed that HIF-1 binding to the consensus hypoxia-responsive element (HRE) sequence resulted in the recruitment of ZBTB2 to the gene locus and increased p300-mediated histone acetylation, leading to enhanced gene expression under hypoxia. In contrast, expression of HIF-1 target genes lacking ZBTB2 peaks, such as carbonic anhydrase 9 (CA9), was not upregulated by ZBTB2. These findings demonstrate that ZBTB2 is a novel factor that can be recruited to the vicinity of HREs on a subset of HIF-1 target gene loci, and is required for their full expression under hypoxia.