EZH2 variants derived from cryptic splice sites govern distinct epigenetic patterns during embryonic development.

Area of Science:

• Molecular Biology
• Developmental Biology
• Epigenetics

Background:

• Enhancer of Zeste Homolog 2 (EZH2) is a key epigenetic regulator catalyzing H3K27me3, essential for embryonic development.
• The functional significance of EZH2 heterogeneity, arising from multiple identified variants, remains largely unexplored.

Purpose of the Study:

• To investigate the functional implications and physiological significance of EZH2 heterogeneity.
• To elucidate the distinct roles of EZH2 variants in embryonic development and gene regulation.

Main Methods:

• Structural modeling to analyze the impact of a 9-amino acid segment on EZH2 structure.
• Generation of point-mutation mouse lines to specifically deplete EZH2A or EZH2B.
• RNA-sequencing and CUT&Tag analyses to assess genomic binding and H3K27me3 deposition.

Main Results:

• Alternative splicing generates two EZH2 variants (EZH2A and EZH2B) differing by a 9-amino acid segment, impacting EZH2 structure and PRC2 complex interaction.
• Depletion of EZH2A leads to developmental defects and embryonic lethality, whereas EZH2B-depleted mice are viable.
• EZH2A and EZH2B exhibit distinct genomic binding patterns, influencing H3K27me3 levels in development-related (Hippo-Yap1 pathway) and innate immunity genes, respectively.

Conclusions:

• EZH2 heterogeneity, driven by alternative splicing of a 9-amino acid region, plays a critical role in embryonic development.
• EZH2A is essential for normal embryonic development, impacting the Hippo-Yap1 pathway, while EZH2B is implicated in innate immunity.
• Distinct functional roles of EZH2 variants highlight the complexity of epigenetic regulation in development and immunity.