The ancient mammalian KRAB zinc finger gene cluster on human chromosome 8q24.3 illustrates principles of C2H2 zinc finger evolution associated with unique expression profiles in human tissues
1 Institute of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany
2 Institute of Bioinformatics, GSF - Research Institute for Environment and Health, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany
3 Theoretical Systems Biology, Institute of Food Research, Norwich Research Park, Norwich NR4 7UH, UK
4 Inserm U830, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France
5 Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05 Paris, France
6 Department of Genome Analysis, Leibniz Institute for Age Research-Fritz Lipmann Institute, Beutenbergstr 11, 07745 Jena, Germany
7 Current address: Institut für Agrar- und Ernährungswissenschaften Martin-Luther-Universität Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany
8 Bioinformatics Center, Key Lab of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Yueyang Road, Shanghai 200031, PR China
BMC Genomics 2010, 11:206 doi:10.1186/1471-2164-11-206Published: 26 March 2010
Expansion of multi-C2H2 domain zinc finger (ZNF) genes, including the Krüppel-associated box (KRAB) subfamily, paralleled the evolution of tetrapodes, particularly in mammalian lineages. Advances in their cataloging and characterization suggest that the functions of the KRAB-ZNF gene family contributed to mammalian speciation.
Here, we characterized the human 8q24.3 ZNF cluster on the genomic, the phylogenetic, the structural and the transcriptome level. Six (ZNF7, ZNF34, ZNF250, ZNF251, ZNF252, ZNF517) of the seven locus members contain exons encoding KRAB domains, one (ZNF16) does not. They form a paralog group in which the encoded KRAB and ZNF protein domains generally share more similarities with each other than with other members of the human ZNF superfamily. The closest relatives with respect to their DNA-binding domain were ZNF7 and ZNF251. The analysis of orthologs in therian mammalian species revealed strong conservation and purifying selection of the KRAB-A and zinc finger domains. These findings underscore structural/functional constraints during evolution. Gene losses in the murine lineage (ZNF16, ZNF34, ZNF252, ZNF517) and potential protein truncations in primates (ZNF252) illustrate ongoing speciation processes. Tissue expression profiling by quantitative real-time PCR showed similar but distinct patterns for all tested ZNF genes with the most prominent expression in fetal brain. Based on accompanying expression signatures in twenty-six other human tissues ZNF34 and ZNF250 revealed the closest expression profiles. Together, the 8q24.3 ZNF genes can be assigned to a cerebellum, a testis or a prostate/thyroid subgroup. These results are consistent with potential functions of the ZNF genes in morphogenesis and differentiation. Promoter regions of the seven 8q24.3 ZNF genes display common characteristics like missing TATA-box, CpG island-association and transcription factor binding site (TFBS) modules. Common TFBS modules partly explain the observed expression pattern similarities.
The ZNF genes at human 8q24.3 form a relatively old mammalian paralog group conserved in eutherian mammals for at least 130 million years. The members persisted after initial duplications by undergoing subfunctionalizations in their expression patterns and target site recognition. KRAB-ZNF mediated repression of transcription might have shaped organogenesis in mammalian ontogeny.