Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression

Orlando IMC, Lafleur VN, Storti F, Spielmann P, Crowther L, Santambrogio S, Schödel J, Hoogewijs D, Mole DR, Wenger RH (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Haematologica

Book Volume: 105

Pages Range: 2774-2784

Journal Issue: 12

DOI: 10.3324/haematol.2019.236406

Abstract

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 EPO gene, 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.

Authors with CRIS profile

Johannes Schödel Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) University of Oxford GB United Kingdom (GB)

How to cite

APA:

Orlando, I.M.C., Lafleur, V.N., Storti, F., Spielmann, P., Crowther, L., Santambrogio, S.,... Wenger, R.H. (2020). Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression. Haematologica, 105(12), 2774-2784. https://doi.org/10.3324/haematol.2019.236406

MLA:

Orlando, Ilaria M. C., et al. "Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression." Haematologica 105.12 (2020): 2774-2784.

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