A histidine cluster determines YY1-compartmentalized coactivators and chromatin elements in phase-separated enhancer...

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• Yin Yang 1 (YY1) is an oncogenic transcription factor regulating enhancer-promoter connections.
• Understanding how YY1 assembles enhancers and super-enhancers with coactivators remains incomplete.

Purpose of the Study:

• To investigate the role of YY1's histidine cluster in phase separation and enhancer complex formation.
• To elucidate the mechanism by which YY1 activates target gene expression.

Main Methods:

• Analysis of YY1's histidine cluster function in phase separation.
• Assays for cell proliferation, migration, and tumor growth.
• Co-immunoprecipitation and fluorescent in situ hybridization (FISH) to identify interacting proteins and gene locus colocalization.

Main Results:

• A histidine cluster in YY1's transactivation domain is essential for phase separation condensates and promoting cancer phenotypes.
• YY1 condensates recruit coactivators (EP300, BRD4, MED1) and active RNA polymerase II, localizing to active gene markers.
• Wild-type YY1, but not a mutant, connects enhancers to the FOXM1 promoter, activating its expression and forming enhancer clusters.

Conclusions:

• YY1 activates gene expression via liquid-liquid phase separation, compartmentalizing coactivators and enhancers.
• The YY1 histidine cluster is a critical determinant for phase separation-driven gene activation and oncogenesis.