MTF2 (metal response element binding transcription factor 2) is a Polycomb-like protein that functions as a key regulatory component of the Polycomb repressive complex 2 (PRC2) 1. MTF2 specifically binds to histone H3 trimethylated at lysine 36 (H3K36me3) and enhances PRC2's histone methyltransferase activity, promoting H3K27me3 methylation for gene silencing 2. The protein stimulates PRC2 chr1-binding activity through DNA-sequence dependent mechanisms, preferentially binding GA-rich sequences 2. MTF2 is essential for PRC2-mediated Hox gene repression during development and collaborates with both PRC2 and PRC1 complexes 1. Paradoxically, MTF2 can also function as a tumor suppressor by activating CDKN2A expression and promoting cellular senescence through local suppression of PRC2 catalytic activity 1. In cancer contexts, MTF2 displays tissue-specific roles, functioning as either a tumor suppressor or oncogene depending on the cellular environment 3. MTF2 dysregulation has been implicated in multiple myeloma 4, esophageal squamous cell carcinoma where its suppression promotes oncogenic pathways 5, and Parkinson's disease risk 6. These context-dependent functions highlight MTF2's complex role in epigenetic regulation and its potential as a therapeutic target.