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ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex

Claudia I. Semprich, View ORCID ProfileVicki Metzis, View ORCID ProfileHarshil Patel, View ORCID ProfileJames Briscoe, View ORCID ProfileKate G. Storey
doi: https://doi.org/10.1101/586719
Claudia I. Semprich
Division of Cell & Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, DD1 5EH, Scotland, UK
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Vicki Metzis
1The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Harshil Patel
2Bioinformatics and Biostatistics, 1 Midland Road, London, NW1 1AT, UK
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James Briscoe
1The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Kate G. Storey
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  • ORCID record for Kate G. Storey
  • For correspondence: k.g.storey@dundee.ac.uk
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Abstract

Fibroblast Growth Factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress FGF signalling has to decline. Why this signalling dynamic is required has not been determined. Here we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly increases chromatin accessibility at neural genes in mouse embryos and, using ATAC-seq in human embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs across hundreds of neural genes. Importantly, while Erk1/2 inhibition induces precocious neural gene transcription, this step involves dissociation of the polycomb repressive complex from gene loci and takes places independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. We find that loss of ERK1/2 activity but not its occupancy at neural genes is critical for this mechanism. Moreover, transient ERK1/2 inhibition is sufficient for polycomb protein dissociation and this is not reversed on resumption of ERK1/2 signalling. These data indicate that ERK1/2 signalling maintains polycomb repressive complexes at neural genes, that its decline coordinates their increased accessibility and that this is a directional molecular mechanism, which initiates the process of neural commitment. Furthermore, as the polycomb repressive complexes repress but also ready genes for transcription, these findings suggest that ERK1/2 promotion of these complexes is a rite of passage for subsequent differentiation.

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Posted April 04, 2019.
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ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex
Claudia I. Semprich, Vicki Metzis, Harshil Patel, James Briscoe, Kate G. Storey
bioRxiv 586719; doi: https://doi.org/10.1101/586719
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ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex
Claudia I. Semprich, Vicki Metzis, Harshil Patel, James Briscoe, Kate G. Storey
bioRxiv 586719; doi: https://doi.org/10.1101/586719

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