1 The Multiple Myeloma SET Domain (MMSET) Protein is a Histone Methyltransferase with Characteristics of a Transcriptional Co-repressor

MMSET, identified by its fusion to the IgH locus in t(4;14) associated multiple myeloma, posses domains found within chromatin regulators including the SET domain. MMSET protein is overexpressed and tighly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20; while MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin–embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetyaltion. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a and the histone demethylase LSD1 suggesting that it is a component of co-repressor complexes