Cross-enhancement of ANGPTL4 transcription by HIF1 alpha and PPAR beta/delta is the result of the conformational proximity of two response elements

Abstract

BackgroundSynergistic transcriptional activation by different stimuli has been reported along with a diverse array of mechanisms, but the full scope of these mechanisms has yet to be elucidated.ResultsWe present a detailed investigation of hypoxia-inducible factor (HIF) 1 dependent gene expression in endothelial cells which suggests the importance of crosstalk between the peroxisome proliferator-activated receptor (PPAR) β/δ and HIF signaling axes. A migration assay shows a synergistic interaction between these two stimuli, and we identify angiopoietin-like 4 (ANGPTL4) as a common target gene by using a combination of microarray and ChIP-seq analysis. We profile changes of histone marks at enhancers under hypoxia, PPARβ/δ agonist and dual stimulations and these suggest that the spatial proximity of two response elements is the principal cause of the synergistic transcription induction. A newly developed quantitative chromosome conformation capture assay shows the quantitative change of the frequency of proximity of the two response elements.ConclusionsTo the best of our knowledge, this is the first report that two different transcription factors cooperate in transcriptional regulation in a synergistic fashion through conformational change of their common target genes.

α1-Antitrypsin Combines with Plasma Fatty Acids and Induces Angiopoietin-like Protein 4 Expression

“…Angptl4 is a potent anti-angiogenic and anti-inflammatory factor, which is under the transcriptional control of PPARγ (50). FABP4 and CD36 are also PPARγ target genes involved in lipid metabolism, and PPARγ activation was found to induce FABP4 mRNA in human monocytes (51).…”

Hypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemia

“…Gene-set differential expression analysis of patient samples at TKI resistance compared with pre-TKI samples showed alterations in hypoxia-related pathways and upregulation of hypoxia response genes such as ANGPTL4 (ref. 20 and Supplemental Table 5). We also found a hypoxia-responsive element (HRE) in the BMX promoter (Figure 3B), and a luciferase reporter assay showed HRE-dependent promoter activity under hypoxic conditions ( Figure 3B).…”

Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells

“…Megabase TADs are reportedly already formed in ES cells and largely conserved through development, among different cell types and in response to specific stimuli (Dixon et al , ; Jin et al , ), although recent studies have suggested that submegabase (sub)‐TADs could have plastic properties (Phillips‐Cremins et al , ; Siersbaek et al , ; Kim et al , ; Ogiyama et al , ). Furthermore, using 3C, circular 3C (4C), and ChIA‐PET, we showed that human ECs have cell type‐specific small chromatin loops, which correlate with gene expression profiles (Kanki et al , ; Mimura et al , ; Papantonis et al , ; Inoue et al , ). However, there is no clear consensus on the plasticity of chromatin interactions ( i.e ., chromatin loops or small TADs) in response to external stimuli, particularly in terminally differentiated cells.…”