The Tumor Suppressor PRDM5 Regulates Wnt Signaling at Early Stages of Zebrafish Development

PRDM genes are a family of transcriptional regulators that modulate cellular processes such as differentiation, cell growth and apoptosis. Some family members are involved in tissue or organ maturation, and are differentially expressed in specific phases of embryonic development. PRDM5 is a recently identified family member that functions as a transcriptional repressor and behaves as a putative tumor suppressor in different types of cancer. Using gene expression profiling, we found that transcriptional targets of PRDM5 in human U2OS cells include critical genes involved in developmental processes, and specifically in regulating wnt signaling. We therefore assessed PRDM5 function in vivo by performing loss-of-function and gain-of-function experiments in zebrafish embryos. Depletion of prdm5 resulted in impairment of morphogenetic movements during gastrulation and increased the occurrence of the masterblind phenotype in axin+/− embryos, characterized by the loss of eyes and telencephalon. Overexpression of PRDM5 mRNA had opposite effects on the development of anterior neural structures, and resulted in embryos with a shorter body axis due to posterior truncation, a bigger head and abnormal somites. In situ hybridization experiments aimed at analyzing the integrity of wnt pathways during gastrulation at the level of the prechordal plate revealed inhibition of non canonical PCP wnt signaling in embryos overexpressing PRDM5, and over-activation of wnt/β-catenin signaling in embryos lacking Prdm5. Our data demonstrate that PRDM5 regulates the expression of components of both canonical and non canonical wnt pathways and negatively modulates wnt signaling in vivo

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Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates

<p>Abstract</p> <p>Background</p> <p>Progressive 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.</p> <p>Results</p> <p>Our 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 <it>PRDM7</it>, acquire tissue-specificity. <it>PRDM7 </it>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), <it>PRDM7 </it>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.</p> <p>Conclusion</p> <p>Our 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.</p

Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates-1

<p><b>Copyright information:</b></p><p>Taken from "Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates"</p><p>http://www.biomedcentral.com/1471-2148/7/187</p><p>BMC Evolutionary Biology 2007;7():187-187.</p><p>Published online 4 Oct 2007</p><p>PMCID:PMC2082429.</p><p></p>yan. and are represented as grey blocks. The chromosome number in the corresponding genome is provided. Dashed lines correspond to regions of break of synteny. Abbreviations: , Homo sapiens; , Pan troglodytes; , Macaca mulatta; , Mus musculus; , Rattus norvegicus; , Gallus gallus. . Since for chimp and macaque no mRNA sequences are available, the human and were used as templates for gene predictions. In chimp, the intron putatively gained by is composed of eight repeats. In the genomic regions corresponding to chimp , there are four additional Zn-Fingers, which are reported in black because there is no evidence for their transcription. The dashed lines represent regions of gaps in the genome assembly. In rodents, the last intron is longer and not in scale; the corresponding length is reported in brackets. . The grey lines represent the genomic regions of segmental duplication. The corresponding chromosome number, chromosomal coordinates and direction of transcription are given. For , the splicing variants present in the database are shown. For , both the database transcripts and the isoforms detected in this study are reported together with an in-silico gene prediction obtained by using the PRDM9 long isoform as template

Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates-0

<p><b>Copyright information:</b></p><p>Taken from "Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates"</p><p>http://www.biomedcentral.com/1471-2148/7/187</p><p>BMC Evolutionary Biology 2007;7():187-187.</p><p>Published online 4 Oct 2007</p><p>PMCID:PMC2082429.</p><p></p>are shown in grey. On main bifurcations, the corresponding posterior probability from Bayesian inference is reported (see Methods). Different colours associated to tree branches correspond to the main subfamilies. For each subfamily, the gene structure of human PRDM ortholog is depicted. The scale refers to exons only. The tree image was produced using iTOL [44]. . PRDM genes are ordered by increasing evolutionary divergence, calculated as cumulative branch lengths from the tip to the root of the phylogenetic tree. The expression data were measured as the mean values of different assays for each gene (see Methods). The upper limit of the 2values was set to 10. For original values see Additional file

Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair

Acute myelogenous leukemias (AMLs) are genetically heterogeneous and characterized by chromosomal rearrangements that produce fusion proteins with aberrant transcriptional regulatory activities. Expression of AML fusion proteins in transgenic mice increases the risk of myeloid leukemias, suggesting that they induce a preleukemic state. The underlying molecular and biological mechanisms are, however, unknown. To address this issue, we performed a systematic analysis of fusion protein transcriptional targets. We expressed AML1/ETO, PML/RAR, and PLZF/RAR in U937 hemopoietic precursor cells and measured global gene expression using oligonucleotide chips. We identified 1,555 genes regulated concordantly by at least two fusion proteins that were further validated in patient samples and finally classified according to available functional information. Strikingly, we found that AML fusion proteins induce genes involved in the maintenance of the stem cell phenotype and repress DNA repair genes, mainly of the base excision repair pathway. Functional studies confirmed that ectopic expression of fusion proteins constitutively activates pathways leading to increased stem cell renewal (e.g., the Jagged1/Notch pathway) and provokes accumulation of DNA damage. We propose that expansion of the stem cell compartment and induction of a mutator phenotype are relevant features underlying the leukemic potential of AML-associated fusion proteins