Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity
Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent ge...
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| Format: | Article |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/24/9401 |
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| author | Antonio Bouthelier Florinda Meléndez-Rodríguez Andrés A. Urrutia Julián Aragonés |
| author_facet | Antonio Bouthelier Florinda Meléndez-Rodríguez Andrés A. Urrutia Julián Aragonés |
| author_sort | Antonio Bouthelier |
| collection | DOAJ |
| description | Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional <i>Vhl</i>-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as <i>CAIX</i> (<i>CAR9</i>) and <i>BNIP3</i>, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier <i>SLC7A5</i>. The HIF selectivity for some genes in WT8 cells is conserved in <i>Vhl</i>-deficient lung and liver tissue, whereas other genes like <i>Glut1</i> (<i>Slc2a1</i>) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed. |
| first_indexed | 2024-03-10T14:10:49Z |
| format | Article |
| id | doaj.art-891871623fec41b1ba863823fb3e5b80 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:10:49Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-891871623fec41b1ba863823fb3e5b802023-11-21T00:10:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012124940110.3390/ijms21249401Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene SelectivityAntonio Bouthelier0Florinda Meléndez-Rodríguez1Andrés A. Urrutia2Julián Aragonés3Research Unit, Hospital Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, 28009 Madrid, SpainResearch Unit, Hospital Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, 28009 Madrid, SpainResearch Unit, Hospital Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, 28009 Madrid, SpainResearch Unit, Hospital Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, 28009 Madrid, SpainCellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional <i>Vhl</i>-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as <i>CAIX</i> (<i>CAR9</i>) and <i>BNIP3</i>, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier <i>SLC7A5</i>. The HIF selectivity for some genes in WT8 cells is conserved in <i>Vhl</i>-deficient lung and liver tissue, whereas other genes like <i>Glut1</i> (<i>Slc2a1</i>) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed.https://www.mdpi.com/1422-0067/21/24/9401oxygenhypoxia-inducible factorsHIF1HIF2transcription |
| spellingShingle | Antonio Bouthelier Florinda Meléndez-Rodríguez Andrés A. Urrutia Julián Aragonés Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity International Journal of Molecular Sciences oxygen hypoxia-inducible factors HIF1 HIF2 transcription |
| title | Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity |
| title_full | Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity |
| title_fullStr | Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity |
| title_full_unstemmed | Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity |
| title_short | Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity |
| title_sort | differential contribution of n and c terminal regions of hif1α and hif2α to their target gene selectivity |
| topic | oxygen hypoxia-inducible factors HIF1 HIF2 transcription |
| url | https://www.mdpi.com/1422-0067/21/24/9401 |
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