Genome-wide analysis reveals NRP1 as a direct HIF1α-E2F7 target in the regulation of motorneuron guidance in vivo

Alain de Bruin, Peter W A Cornelissen, Bettina C Kirchmaier, Michal Mokry, Elhadi Iich, Ella Nirmala, Kuo-Hsuan Liang, Anna M D Végh, Koen T Scholman, Marian J Groot Koerkamp, Frank C Holstege, Edwin Cuppen, Stefan Schulte-Merker, Walbert J Bakker

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Abstract

In this study, we explored the existence of a transcriptional network co-regulated by E2F7 and HIF1α, as we show that expression of E2F7, like HIF1α, is induced in hypoxia, and because of the previously reported ability of E2F7 to interact with HIF1α. Our genome-wide analysis uncovers a transcriptional network that is directly controlled by HIF1α and E2F7, and demonstrates both stimulatory and repressive functions of the HIF1α -E2F7 complex. Among this network we reveal Neuropilin 1 (NRP1) as a HIF1α-E2F7 repressed gene. By performing in vitro and in vivo reporter assays we demonstrate that the HIF1α-E2F7 mediated NRP1 repression depends on a 41 base pairs 'E2F-binding site hub', providing a molecular mechanism for a previously unanticipated role for HIF1α in transcriptional repression. To explore the biological significance of this regulation we performed in situ hybridizations and observed enhanced nrp1a expression in spinal motorneurons (MN) of zebrafish embryos, upon morpholino-inhibition of e2f7/8 or hif1α. Consistent with the chemo-repellent role of nrp1a, morpholino-inhibition of e2f7/8 or hif1α caused MN truncations, which was rescued in TALEN-induced nrp1a(hu10012) mutants, and phenocopied in e2f7/8 mutant zebrafish. Therefore, we conclude that repression of NRP1 by the HIF1α-E2F7 complex regulates MN axon guidance in vivo.

Original languageEnglish
JournalNucleic Acids Research
Early online date17 Dec 2015
DOIs
Publication statusPublished - 05 May 2016

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    de Bruin, A., Cornelissen, P. W. A., Kirchmaier, B. C., Mokry, M., Iich, E., Nirmala, E., Liang, K-H., Végh, A. M. D., Scholman, K. T., Groot Koerkamp, M. J., Holstege, F. C., Cuppen, E., Schulte-Merker, S., & Bakker, W. J. (2016). Genome-wide analysis reveals NRP1 as a direct HIF1α-E2F7 target in the regulation of motorneuron guidance in vivo. Nucleic Acids Research. https://doi.org/10.1093/nar/gkv1471