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

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 must decline. Why these signalling dynamics are 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 genome-wide across neural genes. Importantly, ERK1/2 inhibition induces precocious neural gene transcription, and this involves dissociation of the polycomb repressive complex from key gene loci. This takes place independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. Transient ERK1/2 inhibition is sufficient for the dissociation of the repressive complex, and this is not reversed on resumption of ERK1/2 signalling. Moreover, genomic footprinting of sites identified by ATAC-seq together with ChIP-seq for polycomb protein Ring1B revealed that ERK1/2 inhibition promotes the occupancy of neural transcription factors (TFs) at non-polycomb as well as polycomb associated sites. Together, these findings indicate that ERK1/2 signalling decline promotes global changes in chromatin accessibility and TF binding at neural genes by directing polycomb and other regulators and appears to serve as a gating mechanism that provides directionality to the process of differentiation.

Ascorbic acid and its transporter SVCT2, affect radial glia cells differentiation in postnatal stages

“…In this sense, it has been proposed that GSK3‐β deletion removes homeostatic controls on neural progenitors, shifting the balance toward self‐renewal, massively expanding the radial progenitor pool, and leading away from neurogenesis (Kim et al, 2009). Unexpectedly, we found that the ERK1/2 pathway was decreased in brains with high levels of SVCT2 although it has been shown that overexpression of SVCT2 and treatment with AA promoted ERK1/2 phosphorylation, stimulating neuronal differentiation (Li et al, 2006; Salazar et al, 2016; Semprich et al, 2022). However, it has also been demonstrated that ERK1/2 inhibits neuronal differentiation of neural stem cells (Wang et al, 2009) and upregulates the expression of astrocyte‐related genes (Wang et al, 2016).…”

“…Unexpectedly, we found that the ERK1/2 pathway was decreased in brains with high levels of SVCT2 although it has been shown that overexpression of SVCT2 and treatment with AA promoted ERK1/2 phosphorylation, stimulating neuronal differentiation (Li et al, 2006;Salazar et al, 2016;Semprich et al, 2022). However, it has also been demonstrated that ERK1/2 inhibits neuronal differentiation of neural stem cells (Wang et al, 2009) and upregulates the expression of astrocyte-related genes (Wang et al, 2016).…”

Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

“…One intriguing possibility, supported by previous ChIP-Seq results, is that Cic leaves hkb’s enhancers more slowly than those of tll ( Figure S6 ) (Keenan et al 2020). It is also possible that signaling dependent chromatin changes are involved (Semprich et al 2022; Hannon et al 2017). These models will be tested in future studies.…”

Unravelling differential Hes1 dynamics during axis elongation of mouse embryos through single-cell tracking

“…Therefore, we asked how Hes1 dynamics changed upon induced differentiation. Since FGF inhibition induces differentiation of pre-NT to NT 25,27,52 and PSM to somite 53,54 , we inhibited FGF activity in 2D spread-out cultures using SU5402 (Fig. 6).…”

“…NMPs transitioning from the TB to the NT pass through the preneural tube (pre-NT), surrounded by oscillating PSM 25 . FGF signalling prevents premature differentiation in the pre-NT, while Notch signalling supports cell proliferation 26,27 . In the anterior NT, neural progenitor cells continue to proliferate and differentiate into future spinal cord neurons.…”