An epigenetic program dictates MYC amplification dynamics that promote transient, extrachromosomal, and inherited genomic events.

Epigenetic regulation by KDM4C and SETD2 controls MYC amplification dynamics, promoting extrachromosomal and inherited genomic events in cancer.

• Why it matters: Understanding how MYC amplification arises is crucial because it drives tumor progression and therapy resistance, yet the epigenetic mechanisms behind these copy number changes are poorly understood.
• What they did: The study examined the roles of histone modifications and enzymes, showing that H3K4 methylation primes MYC for amplification, while KDM4C and SETD2 regulate copy gains through their epigenetic activities, with additional insights from tumor datasets.
• The result: Inhibition of KDM4C reduces MYC amplification, and loss of TP53 or suppression of apoptosis accelerates amplification events, highlighting potential targets for limiting MYC-driven tumor growth.