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

Area of Science:

• Developmental Biology
• Molecular Biology
• Epigenetics

Background:

• Fibroblast growth factor (FGF) is a key neural inducer in vertebrate embryos.
• The precise mechanisms by which FGF regulates chromatin organization for neural gene activation remain unclear.
• The necessity for declining FGF signaling dynamics during differentiation is not fully understood.

Purpose of the Study:

• To investigate how FGF signaling dynamics, specifically the decline of ERK1/2 phosphorylation, influence chromatin accessibility and neural gene activation.
• To elucidate the role of ERK1/2 signaling in coordinating the temporal regulation of neural differentiation.
• To determine the impact of ERK1/2 signaling dynamics on the Polycomb Repressive Complex (PRC) and transcription factor binding.

Main Methods:

• ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) in human embryonic stem cell-derived spinal cord precursors.
• Genomic footprinting combined with ChIP-seq (Chromatin Immunoprecipitation sequencing) for Polycomb protein Ring1B.
• ERK1/2 inhibition and resumption experiments in mouse and human embryonic stem cell models.

Main Results:

• Dephosphorylation of ERK1/2 rapidly increases chromatin accessibility genome-wide across neural genes.
• ERK1/2 inhibition leads to precocious neural gene transcription via dissociation of the Polycomb Repressive Complex (PRC).
• ERK1/2 inhibition promotes neural transcription factor binding at both PRC-associated and non-associated sites, independent of H3K27me3 loss.

Conclusions:

• FGF signaling decline, mediated by ERK1/2 dephosphorylation, is a critical gating mechanism for neural differentiation.
• This process involves global chromatin remodeling, PRC dissociation, and enhanced transcription factor occupancy.
• The findings provide insight into how signaling dynamics direct chromatin organization to ensure proper developmental progression.