Unknown,Transcriptomics,Genomics,Proteomics

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Changes in gene expression associated with overexpression of a novel oncogene

ABSTRACT: Oncogenic drivers are still not obvious in a number of human cancers. Identification of oncogenes that contribute to tumorigenic transformation when overexpressed in their wild-type form, either because of gene amplification or due to some other epigenetic changes, is particularly challenging. This study was carried out to understand the gene expression changes associated with overexpression of a novel oncogene, Methyl CpG Binding Protein 2 (MECP2), that we recently uncovered from a genome-scale screen. Immortalized but non-transformed derivatives of human mammary epithelial cells (HMECs) carrying catalytic subunit of human telomerase and SV40 large T and small t antigens, were used as recipient cells for these experiments. We compared changes in gene expression among four different experimental groups: (1) recipient cells overexpressing EGFP (negative control); (2) recipient cells overexpressing MECP2 (our oncogene-of-interest); (3) recipient cells overexpressing activated HRASV12 (which is a classical oncogene); (4) recipient cells overexpressing OTX2 (another known oncogene is medulloblastoma). There were biological duplicates of each experimental group (therefore, with 8 samples in total).

ORGANISM(S): Homo sapiens

SUBMITTER: Manish Neupane

PROVIDER: E-GEOD-61135 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Human oncogenes involved in the development of hematological malignancies have been widely used to model experimental leukemia. Here, we used the fli1 promoter in zebrafish to target the expression of oncogenic HRAS to endothelial cells, including the hemogenic endothelium and observed the development of a myelo-erythroid proliferative disease. In larvae, the pathological phenotype is characterized by some disruption of the vascular system with prominent expansion of the caudal hematopoietic tissue, increase of expression of stem cell markers and myelo-erythroid specific genes and production of a large number of l-plastin leukocytes. In mosaic juveniles, increased number of hematopoietic blasts and arrest of myeloid maturation was found in kidney marrow. Peripheral blood showed delays of erythrocyte maturation and increased number of circulating myeloid progenitors. We found that the abnormal phenotype is associated with a down regulation of the Notch pathway as shown by the decrease of expression of Notch target genes, whereas overexpressing an activated form of Notch together with the oncogene prevents the expansion of the myelo-erythroid compartment. This study identifies the downregulation of the Notch pathway following an oncogenic event in the hemogenic endothelium as an important step in the pathogenesis of myelo-erythroid diseases and describes a number of potential effectors of this transformation. Methods: mRNA profiles of transgenic zebrafish overexpressing the oncogene HRAS in endothelial cells (Tg(fli1ep:GAL4FF)ubs3; Tg(UAS:eGFP-HRASV12)io006); or expressing activate Notch in endothelial cells (Tg(fli1ep:GAL4FF)ubs3; tg(UAS:NICD)kca3) were generated by deep sequencing using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed using the CLC bio Assembly Cell software (version 3.2) and the Ensembl (release 63) predicted cDNAs for the Zv9 genome assembly. qRTM-bM-^@M-^SPCR validation was performed using TaqMan and SYBR Green assays.

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Changes in gene expression associated with overexpression of a novel oncogene

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