Polycomb repressive complex (PRC) 2 functions to repress thousands of target genes, and they are responsible for stem cell differentiation and carcinogenesis. However, how PRC2 are recruited to specific regions of their target genes remains elusive. In Drosophila, nine sequence-specific transcription factors including Zeste have been shown to act as PRC2 recruiters, but little is known about their homologues in mammalian cells, as a straightforward homology search failed to work in most cases. Aided by three-dimensional structure prediction and the use of the genomes of intermediate bridging species, we have identified a new protein, Myb/SANT-Like DNA-Binding Domain-Containing Protein 3 (MSANTD3), as the human homologue of Drosophila Zeste. Gel shift assays indicated that MSANTD3 binds to Zeste recognition sequence via its N-terminal DNA binding domain. MSANTD3 physically interacted with the components of PRC2 in GST-pull down assays and can be co-purified from native mouse P19 cells with active tri-methylation activity. Chip-seq and Chip-qPCR experiments showed the co-localization of MSANTD3 with PRC2 complex on neuron differentiation genes. Together, these findings revealed the critical function of MSANTD3 in recruiting PRC2 complexes to regulate neuron differentiation.