SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development.
Chiang, Ivy Kim-Ni
De Val, Sarah
Company of Biologists
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Chiang, I. K., Fritzsche, M., Pichol-Thievend, C., Neal, A., Holmes, K., Lagendijk, A., Overman, J., et al. (2017). SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development.. Development, 144 (14), 2629-2639. https://doi.org/10.1242/dev.146241
Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.
Arterial enhancer, Artery, Endothelial cell, Human, Mouse, Notch1, SoxF, Transcriptional regulation, Zebrafish, Amino Acid Sequence, Animals, Animals, Genetically Modified, Arteries, Arteriovenous Malformations, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Developmental, Human Umbilical Vein Endothelial Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Pregnancy, Receptor, Notch1, SOXF Transcription Factors, Sequence Homology, Amino Acid, Signal Transduction, Zebrafish, Zebrafish Proteins
This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (APP1107643); The Cancer Council Queensland (1107631) (M.Fran.); the Australian Research Council Discovery Project (DP140100485) and a Career Development Fellowship (APP1111169) (M.Fran.); the Ludwig Institute for Cancer Research (M.Frit., A.N., I.R., S.D.V.); the Medical Research Council (MR/J007765/1) (K.L., G.B.-G., S.D.V.); the Fondazione Cariplo (2011-0555) (M.B., B.H., M.Fran.); and the Biotechnology and Biological Sciences Research Council (BB/L020238/1) (A.N., K.L., G.B.-G., S.D.V.).
Cancer Research UK (C14303_do not transfer)
External DOI: https://doi.org/10.1242/dev.146241
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291858
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