MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• MLL3 (histone H3K4 methyltransferase) is frequently mutated in cancer.
• The molecular mechanisms of MLL3's role in cancer are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which MLL3 suppresses cancer.
• To identify MLL3 target genes and their role in cancer cell migration and proliferation.

Main Methods:

• CRISPR/sgRNA for MLL3 depletion.
• RNA-Sequencing (RNA-Seq) and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) to identify MLL3 targets.
• 3C assay to confirm enhancer-promoter interaction.
• dCas9-KRAB system for enhancer repression.
• Exogenous TNS3 expression in MLL3-deficient cells.

Main Results:

• MLL3 depletion enhanced cancer cell migration but not proliferation.
• TNS3 was identified as a direct MLL3 target gene.
• MLL3 regulates H3K4me1 and H3K27ac marks on a TNS3 enhancer.
• Enhancer-promoter interaction and enhancer activity are crucial for TNS3 expression.
• TNS3 expression reversed the enhanced migration phenotype in MLL3-deficient cells.

Conclusions:

• MLL3 suppresses cancer progression by maintaining TNS3 expression via epigenetic regulation of its enhancer.
• This study reveals a novel mechanism of MLL3 tumor suppression.
• MLL3 and TNS3 represent potential targets for cancer diagnosis and drug development.