A cell with two X chromosomes must silence one to survive. This is done by the Xist gene, a master regulator that coats one X in RNA. But how does Xist KNOW when to turn on—and only in females? 🔬 Our new study reveals a two-step regulatory logic that decodes sex and development.

The Xist switch has two distinct phases: 🔹 Phase 1 (Binary ON/OFF): Early TFs target proximal regulatory elements → They sense X-chromosome number (XX vs XY) to trigger initial Xist upregulation—ensuring female-specific activation.

🔹 Phase 2 (High-Level Boost): Late TFs activate distal enhancers → They drive high Xist RNA levels needed for robust silencing.

🎯 Why It Matters: High Xist Levels are required for silencing the entire chromosome. 🎛️ Using CasTuner and enhancer deletions we show that Xist expression and silencing efficiency are dose-dependent 📈: reduced Xist RNA = impaired X-chromosome silencing