RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restriction-point

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Biology

Background:

• The restriction (R)-point governs the critical cellular decision between proliferation and death.
• Dysregulation of the R-point is a hallmark of nearly all tumors.
• Understanding the molecular mechanisms controlling the R-point is fundamental to cell biology.

Purpose of the Study:

• To identify the molecular mechanisms governing the R-point decision.
• To elucidate the role of RUNX3 in regulating cell cycle progression at the R-point.

Main Methods:

• Chromatin immunoprecipitation followed by sequencing (ChIP-seq) to identify RUNX3 binding sites.
• Analysis of chromatin accessibility and gene expression.
• Investigation of the role of Trithorax group proteins and Polycomb repressor complexes.

Main Results:

• RUNX3 acts as a pioneer factor, binding to target loci upon mitogenic stimulation.
• RUNX3 facilitates R-point progression by initially opening chromatin via Trithorax proteins and cell-cycle regulators.
• Subsequently, RUNX3 closes chromatin via Polycomb repressor complexes, allowing cells to enter S phase.
• Constitutive RAS signaling leads to RUNX3 maintaining R-point genes in an open state, inhibiting cell cycle progression.

Conclusions:

• RUNX3 is a key pioneer factor essential for R-point decision-making.
• RUNX3 orchestrates dynamic chromatin modifications to control cell proliferation versus death.
• RUNX3's function is critical for appropriate cell cycle progression, and its dysregulation by oncogenic signals like RAS contributes to cancer development.