Structural and functional characterization of a novel Polycomb group gene SCML1.

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Polycomb group (PcG) genes encode transcriptional repressors which regulate homeotic (HOX) genes and others, and are involved in so-called cellular memory mechanisms which is essential in the maintenance of cell identity. We isolated and characterized a novel mammalian gene belonging to the PcG genes.The nucleotide sequence analysis of the cDNAs isolated from the mouse, rat, and human brain revealed that the novel gene encoded the protein (863 amino acids) that showed significant similarity in amino acid sequence to the product of Drosophila PcG gene Scm (Sex comb on midleg). In addition, this protein contained four tandem copies of the mbt domains, which were originally reported in the Drosophila tumor suppressor gene l(3)mbt (lethal(3) malignant brain tumor). We initially named this novel gene SCML1 (Scm like-1), but thereafter renamed it Sfmbt for Scm-related gene containing four mbt domains.Cloning and characterization of the mouse Sfmbt gene revealed that the coding sequence comprised 20 exons, dispersed along approximately 40 kb, and was mapped to the proximal part of Chromosome 14. The human Sfmbt gene was mapped to the chromosome 3p21.1.Northern blot analysis showed that the Sfmbt mRNAs were expressed most abundantly in the adult testis, but less intensively in all the mouse tissues and human cell lines examined.Transient over-expression experiments using adenovirus vector indicated that the Sfmbt gene was involved in the regulation of HOXA1 gene expression, and the modification of the cell proliferation rate in U251 human glioma cell line. These functional data well correspond to the structural data of the Sfmbt gene that belongs to the PcG genes and resembles the Drosophila tumor suppressor gene l(3)mbt. To investigate the mutated phenotype of the Sfmbt gene, the experiment on Sfmbt-deficient mice, generated by targeted mutagenesis, is now in progres.