ABSTRACT
The functions of a gene are traditionally annotated textually using either free text (Gene Reference Into Function or GeneRIF) or controlled vocabularies (e.g., Gene Ontology or Disease Ontology). Inspired by the latest word cloud tools developed by the Information Visualization Group at IBM Research, we have prototyped a visual system for capturing gene annotations, which we named Gene Graph Into Function or GeneGIF. Fully developing the GeneGIF system would be a significant effort. To justify the necessity and to specify the design requirements of GeneGIF, we first surveyed the end-user preferences. From 53 responses, we found that a majority (64%, p < 0.05) of the users were either positive or neutral toward using GeneGIF in their daily work (acceptance); in terms of preference, a slight majority (51%, p > 0.05) of the users favored visual presentation of information (GeneGIF) compared to textual (GeneRIF) information. The results of this study indicate that a visual presentation tool, such as GeneGIF, can complement standard textual presentation of gene annotations. Moreover, the survey participants provided many constructive comments that will specify the development of a phase-two project (http://128.248.174.241/) to visually annotate each gene in the human genome.
Subject(s)
Computer Graphics , Molecular Sequence Annotation/statistics & numerical data , Algorithms , Computational Biology , Data Collection , Databases, Genetic , Humans , Software , User-Computer Interface , Vocabulary, ControlledABSTRACT
The t(11;17)(q23;q21) translocation is associated with a retinoic acid (RA)-insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor alpha (PLZF-RARalpha) and RARalpha-PLZF. Using a combination of chromatin immunoprecipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RARalpha that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RARalpha as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RARalpha promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RARalpha binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RARalpha may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RARalpha-transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RARalpha.
Subject(s)
Cell Proliferation , Genome, Human/genetics , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Proteins c-myc/genetics , Animals , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Cell Survival/genetics , Cell Survival/physiology , Chromatin Immunoprecipitation , Cyclin-Dependent Kinase Inhibitor p19/genetics , Cyclin-Dependent Kinase Inhibitor p19/metabolism , Dual Specificity Phosphatase 6/genetics , Dual Specificity Phosphatase 6/metabolism , Gene Expression Profiling , Gene Expression Regulation, Leukemic/drug effects , Genome-Wide Association Study , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/metabolism , Leukemia, Promyelocytic, Acute/pathology , Mice , Oligonucleotide Array Sequence Analysis , Oncogene Proteins, Fusion/metabolism , Oncogene Proteins, Fusion/physiology , Protein Binding , Proto-Oncogene Proteins c-myc/metabolism , Tretinoin/pharmacology , U937 Cells , Xenograft Model Antitumor AssaysABSTRACT
WT1, a critical regulator of kidney development, is a tumor suppressor for nephroblastoma but in some contexts functions as an oncogene. A limited number of direct transcriptional targets of WT1 have been identified to explain its complex roles in tumorigenesis and organogenesis. In this study we performed genome-wide screening for direct WT1 targets, using a combination of ChIP-ChIP and expression arrays. Promoter regions bound by WT1 were highly G-rich and resembled the sites for a number of other widely expressed transcription factors such as SP1, MAZ, and ZNF219. Genes directly regulated by WT1 were implicated in MAPK signaling, axon guidance, and Wnt pathways. Among directly bound and regulated genes by WT1, nine were identified in the Wnt signaling pathway, suggesting that WT1 modulates a subset of Wnt components and responsive genes by direct binding. To prove the biological importance of the interplay between WT1 and Wnt signaling, we showed that WT1 blocked the ability of Wnt8 to induce a secondary body axis during Xenopus embryonic development. WT1 inhibited TCF-mediated transcription activated by Wnt ligand, wild type and mutant, stabilized beta-catenin by preventing TCF4 loading onto a promoter. This was neither due to direct binding of WT1 to the TCF binding site nor to interaction between WT1 and TCF4, but by competition of WT1 and TCF4 for CBP. WT1 interference with Wnt signaling represents an important mode of its action relevant to the suppression of tumor growth and guidance of development.
