UTX condensation underlies its tumour-suppressive activity

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Biology

Background:

• UTX (KDM6A) is a histone demethylase and tumor suppressor frequently mutated in cancers.
• The demethylase activity of UTX is often not required for its tumor suppressive roles, indicating an unknown molecular mechanism.

Purpose of the Study:

• To elucidate the molecular mechanism underlying UTX's tumor suppressive activity.
• To investigate the role of phase separation in UTX's chromatin-regulatory functions.

Main Methods:

• In vitro and in vivo assays using deletion, mutagenesis, and replacement of UTX's intrinsically disordered region.
• Reconstitution experiments in vitro and engineered systems in cells.
• Analysis of histone modifications and chromatin interactions.

Main Results:

• UTX undergoes phase separation via its core intrinsically disordered region (cIDR), forming liquid condensates.
• Loss of cIDR due to cancer mutations abolishes UTX's tumor suppressive activity.
• UTX condensation is critical for tumor suppression and embryonic stem cell differentiation.
• UTX recruits and enhances the activity of MLL4 (KMT2D) within these condensates.
• UTX regulates genome-wide histone modifications and chromatin interactions in a condensation-dependent manner.
• UTY, a homolog of UTX, forms less dynamic condensates, correlating with weaker tumor suppression.

Conclusions:

• Phase separation of UTX is essential for its chromatin-regulatory activity and tumor suppressive function.
• The material state of UTX condensates is crucial for its biological activity.
• This study reveals a novel mechanism for tumor suppression mediated by the phase separation of chromatin regulators.