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

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 transcriptio...

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Published in:Nucleic acids research 2016-05, Vol.44 (8), p.3549-3566
Main Authors: de Bruin, Alain, A Cornelissen, Peter W, Kirchmaier, Bettina C, Mokry, Michal, Iich, Elhadi, Nirmala, Ella, Liang, Kuo-Hsuan, D Végh, Anna M, Scholman, Koen T, Groot Koerkamp, Marian J, Holstege, Frank C, Cuppen, Edwin, Schulte-Merker, Stefan, Bakker, Walbert J
Format: Article
Language:English
Subjects:
Animals
Axon Guidance - genetics
Binding Sites
Cell Hypoxia - genetics
Cell Line, Tumor
Danio rerio
E2F7 Transcription Factor - genetics
E2F7 Transcription Factor - metabolism
Gene regulation, Chromatin and Epigenetics
Genome-Wide Association Study
HeLa Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
In Situ Hybridization
Morpholinos - genetics
Motor Neurons - metabolism
Neuropilin-1 - genetics
Neuropilin-1 - metabolism
RNA Interference
RNA, Small Interfering - genetics
Transcription, Genetic - genetics
Zebrafish - embryology
Zebrafish - genetics
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkv1471