Integrative Multi-Omics Analysis of Oncogenic EZH2 Mutants: From Epigenetic Reprogramming to Molecular Signatures

Area of Science:

• Epigenetics and Molecular Biology
• Cancer Genomics
• Systems Biology

Background:

• Somatic heterozygous mutations in enhancer of zeste homolog 2 (EZH2) are common in diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML).
• These mutations disrupt EZH2's methyltransferase activity, affecting histone H3 lysine 27 (H3K27) methylation and downstream cellular functions.
• Gain-of-function (GOF) and loss-of-function (LOF) mutations alter chromatin structure, protein interactions, and gene transcription.

Purpose of the Study:

• To comprehensively characterize the multi-omics effects of differential H3K27me3 deposition caused by specific EZH2 mutations.
• To identify genes, protein networks, and metabolic pathways affected by EZH2 GOF and LOF mutants.
• To elucidate EZH2-mediated cell transformation from epigenetic changes to phenotypic outcomes in hematologic malignancies.

Main Methods:

• Utilized a multi-omics approach including EpiProfile, H3K27me3 CUT&Tag, ATAC-Seq, transcriptomics, proteomics, and metabolomics.
• Examined three stable isogenic EZH2 mutants: Y641F (GOF), A677G (LOF), and H689A/F667I (LOF).
• Performed systems biology analysis to integrate epigenetic, transcriptomic, proteomic, and metabolomic data.

Main Results:

• Identified distinct sets of genes and downstream targets affected by EZH2 GOF and LOF mutants.
• Observed impacts on critical cellular pathways including proliferation, differentiation, and migration.
• Revealed disruptions in protein networks and metabolic signatures that support aberrant cell behavior.

Conclusions:

• EZH2 mutations drive significant epigenetic and phenotypic alterations in hematologic malignancies.
• The study provides a systems-level understanding of how mutated EZH2 affects cellular processes.
• Identified potential targets for improved diagnostics and treatments for EZH2-mutated hematologic cancers.