Dynamic lineage priming is driven via direct enhancer regulation by ERK

Area of Science:

• Cellular Biology
• Developmental Biology
• Molecular Biology

Background:

• Cellular state transitions are fundamental to multicellular organism development.
• Fibroblast growth factor-extracellular signal-regulated kinase (FGF-ERK) signaling influences embryonic stem cell (ES cell) differentiation and self-renewal.
• ERK signaling can induce reversible heterogeneity in cell populations, allowing cells to transition between pluripotency and differentiation states.

Purpose of the Study:

• To investigate the molecular mechanisms by which ERK signaling regulates transcription in ES cells.
• To determine how ERK signaling affects enhancer activity and gene expression.
• To understand the role of transcription factor binding and mediator components in ERK-dependent transcriptional regulation and cell fate commitment.

Main Methods:

• Analysis of gene transcription and enhancer activity in mouse embryonic stem cells.
• Investigation of RNA polymerase II and co-factor dynamics at genes and enhancers.
• Assessment of the role of the mediator component MED24 in ERK signaling pathways.
• Examination of pluripotency transcription factor binding dynamics under varying ERK signaling conditions.

Main Results:

• ERK signaling reversibly regulates transcription in ES cells by directly impacting enhancer activity, independent of transcription factor binding changes.
• ERK signaling controls the dynamic association and dissociation of RNA polymerase II and co-factors at genes and enhancers, with MED24 playing a key role.
• Persistent binding of pluripotency factors maintains gene accessibility for reactivation, preserving cellular plasticity.
• Sustained ERK signaling leads to reduced pluripotency factor levels, irreversible gene silencing, and cell fate commitment.

Conclusions:

• ERK signaling acts as a critical regulator of transcriptional plasticity in ES cells, balancing self-renewal and differentiation.
• The dynamic interplay between signaling pathways, transcription factors, and the mediator complex governs cell fate decisions.
• Maintaining pluripotency factor occupancy is essential for cellular responsiveness to transient signals, while sustained signaling drives irreversible commitment.