RESUMEN
The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.
Asunto(s)
Genoma/genética , Genómica , Ratones/genética , Anotación de Secuencia Molecular , Animales , Linaje de la Célula/genética , Cromatina/genética , Cromatina/metabolismo , Secuencia Conservada/genética , Replicación del ADN/genética , Desoxirribonucleasa I/metabolismo , Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Estudio de Asociación del Genoma Completo , Humanos , ARN/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Especificidad de la Especie , Factores de Transcripción/metabolismo , Transcriptoma/genéticaRESUMEN
Representational difference analysis (RDA) of human breast cancer was used to discover a novel amplicon located at chromosomal region 8q24.3. We examined a series of breast cancer samples harboring amplification of this region and determined that KCNK9 is the sole overexpressed gene within the amplification epicenter. KCNK9 encodes a potassium channel that is amplified from 3-fold to 10-fold in 10% of breast tumors and overexpressed from 5-fold to over 100-fold in 44% of breast tumors. Overexpression of KCNK9 in cell lines promotes tumor formation and confers resistance to both hypoxia and serum deprivation, suggesting that its amplification and overexpression plays a physiologically important role in human breast cancer.
Asunto(s)
Amplificación de Genes , Canales de Potasio/genética , Canales de Potasio/metabolismo , Animales , Neoplasias de la Mama/genética , Línea Celular , Trasplante de Células , Cromosomas Humanos Par 8 , Sondas de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Humanos , Ratones , Datos de Secuencia Molecular , Oncogenes , Mapeo Físico de Cromosoma , Lugares Marcados de Secuencia , Trasplante HeterólogoRESUMEN
Mice have been a long-standing model for human biology and disease. Here we characterize, by RNA sequencing, the transcriptional profiles of a large and heterogeneous collection of mouse tissues, augmenting the mouse transcriptome with thousands of novel transcript candidates. Comparison with transcriptome profiles in human cell lines reveals substantial conservation of transcriptional programmes, and uncovers a distinct class of genes with levels of expression that have been constrained early in vertebrate evolution. This core set of genes captures a substantial fraction of the transcriptional output of mammalian cells, and participates in basic functional and structural housekeeping processes common to all cell types. Perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer. Evolutionary constraint in gene expression levels is not reflected in the conservation of the genomic sequences, but is associated with conserved epigenetic marking, as well as with characteristic post-transcriptional regulatory programme, in which sub-cellular localization and alternative splicing play comparatively large roles.
Asunto(s)
Evolución Molecular , Regulación de la Expresión Génica , Transcriptoma , Empalme Alternativo , Animales , Evolución Biológica , Línea Celular , Epigénesis Genética , Perfilación de la Expresión Génica , Biblioteca de Genes , Genoma , Histonas/química , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Genéticos , Oligonucleótidos Antisentido , Fenotipo , Análisis de Secuencia de ARNRESUMEN
Metastasis of primary tumors leads to a very poor prognosis for patients suffering from cancer. Although it is well established that not every tumor will eventually metastasize, it is less clear whether primary tumors acquire genetic alterations in a stochastic process at a late stage, which make them invasive, or whether genetic alterations acquired early in the process of tumor development drive primary tumor growth and determine whether this tumor is going to be metastatic. To address this issue, we tested genes identified in a large-scale comparative genomic hybridization analysis of primary tumor for their ability to confer metastatic properties on a cancer cell. We identified amplification of the ACK1 gene in primary tumors, which correlates with poor prognosis. We further show that overexpression of Ack1 in cancer cell lines can increase the invasive phenotype of these cells both in vitro and in vivo and leads to increased mortality in a mouse model of metastasis. Biochemical studies show that Ack1 is involved in extracellular matrix-induced integrin signaling, ultimately activating signaling processes like the activation of the small GTPase Rac. Taken together, this study supports a theory from Bernards and Weinberg [Bernards, R. & Weinberg, R. A. (2002) Nature 418, 823], which postulates that the tendency to metastasize is largely predetermined.