BackgroundProgressive diversification of paralogs after gene expansion is essential to increase their functional specialization. However, mode and tempo of this divergence remain mostly unclear. Here we report the comparative analysis of PRDM genes, a family of putative transcriptional regulators involved in human tumorigenesis.ResultsOur analysis assessed that the PRDM genes originated in metazoans, expanded in vertebrates and further duplicated in primates. We experimentally showed that fast-evolving paralogs are poorly expressed, and that the most recent duplicates, such as primate-specific PRDM7, acquire tissue-specificity. PRDM7 underwent major structural rearrangements that decreased the number of encoded Zn-Fingers and modified gene splicing. Through internal duplication and activation of a non-canonical splice site (GC-AG), PRDM7 can acquire a novel intron. We also detected an alternative isoform that can retain the intron in the mature transcript and that is predominantly expressed in human melanocytes.ConclusionOur findings show that (a) molecular evolution of paralogs correlates with their expression pattern; (b) gene diversification is obtained through massive genomic rearrangements; and (c) splicing modification contributes to the functional specialization of novel genes.
The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of speci®c chromosome translocations. Of the two components of each fusion protein, one is generally a transcription factor, whereas the other partner is more variable in function, but often involved in the control of cell survival and apoptosis. As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid di erentiation, determine a stagespeci®c arrest of maturation and enhance cell survival in a cell-type speci®c manner. The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant corepressor complexes, alterations in chromatin remodeling, and disruption of speci®c subnuclear compartments. The identi®cation and analysis of common and speci®c target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-speci®c drug design. Oncogene (2001) 20, 5680 ± 5694.
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