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.Reportar como inadecuado




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. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 Institute of Immunology 2 Institute of Bioinformatics 3 Theoretical Systems Biology 4 Unité de génétique et biologie des cancers 5 Service de Génétique Oncologique 6 Department of Genome Analysis 7 Bioinformatics Center

Abstract : BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.





Autor: Peter Lorenz - Sabine Dietmann - Thomas Wilhelm - Dirk Koczan - Sandra Autran - Sophie Gad - Gaiping Wen - Guohui Ding - Yixue Li

Fuente: https://hal.archives-ouvertes.fr/



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