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Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression
While it has been well-established that distal hypoxia response elements (HRE) regulate hypoxia-inducible factor (HIF) target genes such as erythropoietin (Epo), an interplay between multiple distal and proximal (promoter) HRE has not yet been described. Hepatic Epo expression is regulated by an HRE...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716368/ https://www.ncbi.nlm.nih.gov/pubmed/33256376 http://dx.doi.org/10.3324/haematol.2019.236406 |
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author | Orlando, Ilaria M. C. Lafleur, Véronique N. Storti, Federica Spielmann, Patrick Crowther, Lisa Santambrogio, Sara Schödel, Johannes Hoogewijs, David Mole, David R. Wenger, Roland H. |
author_facet | Orlando, Ilaria M. C. Lafleur, Véronique N. Storti, Federica Spielmann, Patrick Crowther, Lisa Santambrogio, Sara Schödel, Johannes Hoogewijs, David Mole, David R. Wenger, Roland H. |
author_sort | Orlando, Ilaria M. C. |
collection | PubMed |
description | While it has been well-established that distal hypoxia response elements (HRE) regulate hypoxia-inducible factor (HIF) target genes such as erythropoietin (Epo), an interplay between multiple distal and proximal (promoter) HRE has not yet been described. Hepatic Epo expression is regulated by an HRE located downstream of the EPOgene, but this 3' HRE is not essential for renal EPO gene expression. We previously identified a 5' HRE and could show that both HRE direct exogenous reporter gene expression. Here, we show that, whereas in hepatic cells the 3' but not the 5' HRE is required, in neuronal cells both the 5' and 3' HRE contribute to endogenous Epo induction. Moreover, two novel putative HRE were identified in the EPO promoter. In hepatoma cells, HIF interacted mainly with the distal 3' HRE, but in neuronal cells, HIF most strongly bound the promoter, bound to a lesser extent the 3' HRE, and did not bind the 5' HRE. Interestingly, mutation of either of the two distal HRE abrogated HIF binding to the 3' and promoter HRE. These results suggest that a canonical functional HRE can recruit multiple transcription factors (not necessarily HIF) to mediate HIF binding to different distant HRE in an organ-specific manner. |
format | Online Article Text |
id | pubmed-7716368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-77163682020-12-10 Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression Orlando, Ilaria M. C. Lafleur, Véronique N. Storti, Federica Spielmann, Patrick Crowther, Lisa Santambrogio, Sara Schödel, Johannes Hoogewijs, David Mole, David R. Wenger, Roland H. Haematologica Article While it has been well-established that distal hypoxia response elements (HRE) regulate hypoxia-inducible factor (HIF) target genes such as erythropoietin (Epo), an interplay between multiple distal and proximal (promoter) HRE has not yet been described. Hepatic Epo expression is regulated by an HRE located downstream of the EPOgene, but this 3' HRE is not essential for renal EPO gene expression. We previously identified a 5' HRE and could show that both HRE direct exogenous reporter gene expression. Here, we show that, whereas in hepatic cells the 3' but not the 5' HRE is required, in neuronal cells both the 5' and 3' HRE contribute to endogenous Epo induction. Moreover, two novel putative HRE were identified in the EPO promoter. In hepatoma cells, HIF interacted mainly with the distal 3' HRE, but in neuronal cells, HIF most strongly bound the promoter, bound to a lesser extent the 3' HRE, and did not bind the 5' HRE. Interestingly, mutation of either of the two distal HRE abrogated HIF binding to the 3' and promoter HRE. These results suggest that a canonical functional HRE can recruit multiple transcription factors (not necessarily HIF) to mediate HIF binding to different distant HRE in an organ-specific manner. Fondazione Ferrata Storti 2019-12-19 /pmc/articles/PMC7716368/ /pubmed/33256376 http://dx.doi.org/10.3324/haematol.2019.236406 Text en Copyright© 2020 Ferrata Storti Foundation http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article Orlando, Ilaria M. C. Lafleur, Véronique N. Storti, Federica Spielmann, Patrick Crowther, Lisa Santambrogio, Sara Schödel, Johannes Hoogewijs, David Mole, David R. Wenger, Roland H. Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression |
title | Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression |
title_full | Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression |
title_fullStr | Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression |
title_full_unstemmed | Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression |
title_short | Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression |
title_sort | distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716368/ https://www.ncbi.nlm.nih.gov/pubmed/33256376 http://dx.doi.org/10.3324/haematol.2019.236406 |
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