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1.
Oncogene ; 32(21): 2640-8, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-22751132

RESUMO

AT-rich interaction domain molecule 3B (ARID3B) and MYCN are expressed in a portion of neuroblastoma, and form a combination that has strong oncogenic activity in mouse embryonic fibroblasts (MEFs). Here, we show that this combination can also convert neural stem cells to neuroblastoma-like tumor. To address whether there are common mechanisms regulating the expression of this combination of genes, we examined public repositories of gene expression data and found that although these genes are rarely expressed together, co-expression was observed in a proportion of germ cell tumors (GCTs), in embryonic stem (ES) cells and in testis. These cell types and tissues are related to pluripotency and we show here that in mouse ES cells, Arid3b and Mycn are indeed involved in cell proliferation; the former in avoiding cell death and the latter in driving cell cycle progression. Accordingly, the two genes are induced during somatic cell reprogramming to iPS, and this induction is accompanied by the switching of promoter histone marks from H3K27me3 to H3K4me3. Conversely, the switch from H3K4me3 to H3K27me3 in these genes occurs during the differentiation of neural crest to mature sympathetic ganglia cells. In many, if not most, neuroblastomas these genes carry H3K4me3 marks within their promoters. Thus, a failure of the epigenetic silencing of these genes during development may be an underlying factor responsible for neuroblastoma.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neuroblastoma/metabolismo , Proteínas Nucleares/biossíntese , Proteínas Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Animais , Ciclo Celular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/patologia , Gânglios Simpáticos/embriologia , Gânglios Simpáticos/patologia , Histonas/genética , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Camundongos , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Crista Neural/embriologia , Crista Neural/patologia , Neuroblastoma/genética , Neuroblastoma/patologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas/genética
2.
Genome Res ; 11(1): 112-23, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11156620

RESUMO

Large-scale gene expression studies and genomic sequencing projects are providing vast amounts of information that can be used to identify or predict cellular regulatory processes. Genes can be clustered on the basis of the similarity of their expression profiles or function and these clusters are likely to contain genes that are regulated by the same transcription factors. Searches for cis-regulatory elements can then be undertaken in the noncoding regions of the clustered genes. However, it is necessary to assess the efficiency of both the gene clustering and the postulated regulatory motifs, as there are many difficulties associated with clustering and determining the functional relevance of matches to sequence motifs. We have developed a method to assess the potential functional significance of clusters and motifs based on the probability of finding a certain number of matches to a motif in all of the gene clusters. To avoid problems with threshold scores for a match, the top matches to a motif are taken in several sample sizes. Genes from a sample are then counted by the cluster in which they appear. The probability of observing these counts by chance is calculated using the hypergeometric distribution. Because of the multiple sample sizes, strong and weak matching motifs can be detected and refined and significant matches to motifs across cluster boundaries are observed as all clusters are considered. By applying this method to many motifs and to a cluster set of yeast genes, we detected a similarity between Swi Five Factor and forkhead proteins and suggest that the currently unidentified Swi Five Factor is one of the yeast forkhead proteins.


Assuntos
Perfilação da Expressão Gênica/métodos , Família Multigênica/genética , Motivos de Aminoácidos/genética , Animais , Ciclo Celular/genética , Biologia Computacional/métodos , Bases de Dados Factuais , Drosophila melanogaster/genética , Fatores de Transcrição Forkhead , Sequências Hélice-Alça-Hélice/genética , Humanos , Camundongos , Proteínas Nucleares/genética , Ratos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Fatores de Transcrição/genética , Xenopus laevis/genética
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