Biomedical subjects

Xijin Ge

Publications and source records attributed to Xijin Ge.

13 recordsLinked to original sources

PubMed2006

SAGE detects microRNA precursors.

BACKGROUND: MicroRNAs (miRNAs) have been shown to play important roles in regulating gene expression. Since miRNAs are often evolutionarily conserved and their precursors can be folded into stem-loop hairpins, many miRNAs have been predicted. Yet experimental confirmation is difficult since miRNA expression is often specific to particular tissues and developmental stages. RESULTS: Analysis of 29 human and 230 mouse longSAGE libraries revealed the expression of 22 known and 10 predicted mammalian miRNAs. Most were detected in embryonic tissues. Four SAGE tags detected in human embryonic stem cells specifically match a cluster of four human miRNAs (mir-302a, b, c&d) known to be expressed in embryonic stem cells. LongSAGE data also suggest the existence of a mouse homolog of human and rat mir-493. CONCLUSION: The observation that some orphan longSAGE tags uniquely match miRNA precursors provides information about the expression of some known and predicted miRNAs.

Animals↗

PubMed2006

A large quantity of novel human antisense transcripts detected by LongSAGE.

MOTIVATION: Taking advantage of the high sensitivity and specificity of LongSAGE tag for transcript detection and genome mapping, we analyzed the 632 813 unique human LongSAGE tags deposited in public databases to identify novel human antisense transcripts. RESULTS: Our study identified 45 321 tags that match the antisense strand of 9804 known mRNA sequences, 6606 of which contain antisense ESTs and 3198 are mapped only by SAGE tags. Quantitative analysis showed that the detected antisense transcripts are present at levels lower than their counterpart sense transcripts. Experimental results confirmed the presence of antisense transcripts detected by the antisense tags. We also constructed an antisense tag database that can be used to identify the antisense SAGE tags originated from the antisense strand of known mRNA sequences included in the RefSeq database. CONCLUSIONS: Our study highlights the benefits of exploring SAGE data for comprehensive identification of human antisense transcripts and demonstrates the prevalence of antisense transcripts in the human genome.

Base Sequence↗

PubMed2006

Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Several studies have identified signature gene sets that may be useful as potential diagnostic tools by global microarray analysis. Here we report the cloning and characterization of a novel gene, lin-28 homolog B (LIN28B), which is overexpressed in hepatocellular carcinoma. The heterochronic gene lin-28 is a key regulator of developmental timing in the nematode Caenorhabditis elegans. Similar with lin-28 proteins, LIN28B conserves a cold shock domain and a pair of CCHC zinc finger domains. Phylogenetic analysis suggests that they might arise as a result of duplication from an ancestral gene. Overexpression of LIN28B was noted in most HCC cell lines and clinical samples. By western blot analysis using a polyclonal antibody against LIN28B, a short LIN28B isoform was also identified in non-tumor liver tissue and fetal liver. Although predominantly localized in the cytoplasm, we found that LIN28B protein shows cell cycle-dependent nuclear translocation in Huh7 cells. Induced expression of exogenous LIN28B in a tet-off cell line promoted cancer cell proliferation. Interestingly, the segment of the unusually long 3'UTR of LIN28B contains complementary sites to let-7 microRNA of mammals. And our studies provided indirect evidence that LIN28B is a possibly natural target for let-7 mediated regulation. These findings strongly implicate a critical role of LIN28B during development and tumorigenesis and suggest a possible novel mechanism.

3' Untranslated Regions↗

PubMed2006

Gene expression profiles in acute myeloid leukemia with common translocations using SAGE.

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15(+) myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15(+) cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy.

Apoptosis↗

PubMed2005

Elevated expression and potential roles of human Sp5, a member of Sp transcription factor family, in human cancers.

In this report, we describe the expression and function of human Sp5, a member of the Sp family of zinc finger transcription factors. Like other family members, the Sp5 protein contains a Cys2His2 zinc finger DNA binding domain at the C-terminus. Our experiments employing Gal4-Sp5 fusion proteins reveal multiple transcriptional domains, including a N-terminal activity domain, an intrinsic repressive element, and a C-terminal synergistic domain. Elevated expression of Sp5 was noted in several human tumors including hepatocellular carcinoma, gastric cancer, and colon cancer. To study the effects of the Sp5 protein on growth properties of human cancer cells and facilitate the identification of its downstream genes, we combined an inducible gene expression system with microarray analysis to screen for its transcriptional targets. Transfer of Sp5 into MCF-7 cells that expressed no detectable endogenous Sp5 protein elicited significant growth promotion activity. Several of the constitutively deregulated genes have been associated with tumorigenesis (CDC25C, CEACAM6, TMPRSS2, XBP1, MYBL1, ABHD2, and CXCL12) and Wnt/beta-Catenin signaling pathways (BAMBI, SIX1, IGFBP5, AES, and p21WAF1). This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against human cancers.

Animals↗

PubMed2005

Annotating nonspecific SAGE tags with microarray data.

SAGE (serial analysis of gene expression) detects transcripts by extracting short tags from the transcripts. Because of the limited length, many SAGE tags are shared by transcripts from different genes. Relying on sequence information in the general gene expression database has limited power to solve this problem due to the highly heterogeneous nature of the deposited sequences. Considering that the complexity of gene expression at a single tissue level should be much simpler than that in the general expression database, we reasoned that by restricting gene expression to tissue level, the accuracy of gene annotation for the nonspecific SAGE tags should be significantly improved. To test the idea, we developed a tissue-specific SAGE annotation database based on microarray data (). This database contains microarray expression information represented as UniGene clusters for 73 normal human tissues and 18 cancer tissues and cell lines. The nonspecific SAGE tag is first matched to the database by the same tissue type used by both SAGE and microarray analysis; then the multiple UniGene clusters assigned to the nonspecific SAGE tag are searched in the database under the matched tissue type. The UniGene cluster presented solely or at higher expression levels in the database is annotated to represent the specific gene for the nonspecific SAGE tags. The accuracy of gene annotation by this database was largely confirmed by experimental data. Our study shows that microarray data provide a useful source for annotating the nonspecific SAGE tags.

Cell Line↗

PubMed2005

2.45 GHz radiofrequency fields alter gene expression in cultured human cells.

The biological effect of radiofrequency (RF) fields remains controversial. We address this issue by examining whether RF fields can cause changes in gene expression. We used the pulsed RF fields at a frequency of 2.45 GHz that is commonly used in telecommunication to expose cultured human HL-60 cells. We used the serial analysis of gene expression (SAGE) method to measure the RF effect on gene expression at the genome level. We observed that 221 genes altered their expression after a 2-h exposure. The number of affected genes increased to 759 after a 6-h exposure. Functional classification of the affected genes reveals that apoptosis-related genes were among the upregulated ones and the cell cycle genes among the downregulated ones. We observed no significant increase in the expression of heat shock genes. These results indicate that the RF fields at 2.45 GHz can alter gene expression in cultured human cells through non-thermal mechanism.

Dose-Response Relationship, Radiation↗

PubMed2005

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues.

A critical and difficult part of studying cancer with DNA microarrays is data interpretation. Besides the need for data analysis algorithms, integration of additional information about genes might be useful. We performed genome-wide expression profiling of 36 types of normal human tissues and identified 2503 tissue-specific genes. We then systematically studied the expression of these genes in cancers by reanalyzing a large collection of published DNA microarray datasets. We observed that the expression level of liver-specific genes in hepatocellular carcinoma (HCC) correlates with the clinically defined degree of tumor differentiation. Through unsupervised clustering of tissue-specific genes differentially expressed in tumors, we extracted expression patterns that are characteristic of individual cell types, uncovering differences in cell lineage among tumor subtypes. We were able to detect the expression signature of hepatocytes in HCC, neuron cells in medulloblastoma, glia cells in glioma, basal and luminal epithelial cells in breast tumors, and various cell types in lung cancer samples. We also demonstrated that tissue-specific expression signatures are useful in locating the origin of metastatic tumors. Our study shows that integration of each gene's breadth of expression (BOE) in normal tissues is important for biological interpretation of the expression profiles of cancers in terms of tumor differentiation, cell lineage, and metastasis.

Algorithms↗

PubMed2004

Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis.

Activation and dysfunction of the endothelium underlie many vascular disorders including atherosclerosis, tumor growth, and inflammation. Endothelial cell activation is mediated by many different extra-cellular signals, which result in overlapping yet distinct patterns of gene expression. Here we show, in DNA microarray analyses, that vascular endothelial growth factor (VEGF) and thrombin result in dramatic and rapid upregulation of Down syndrome critical region (DSCR)-1 gene encoding exons 4-7, a negative feedback regulator of calcium-calcineurin-NF-AT signaling. VEGF- and thrombin-mediated induction of DSCR-1 involves the cooperative binding of NF-ATc and GATA-2/3 to neighboring consensus motifs in the upstream promoter. Constitutive expression of DSCR-1 in endothelial cells markedly impaired NF-ATc nuclear localization, proliferation, and tube formation. Under in vivo conditions, overexpression of DSCR-1 reduced vascular density in matrigel plugs and melanoma tumor growth in mice. Taken together, these findings support a model in which VEGF- and thrombin-mediated induction of endothelial cell proliferation triggers a negative feedback loop consisting of DSCR-1 gene induction and secondary inhibition of NF-AT signaling. As a natural brake in the angiogenic process, this negative pathway may lend itself to therapeutic manipulation in pathological states.

Animals↗

PubMed2004

Selective expression of a subset of neuronal genes in oligodendroglioma with chromosome 1p loss.

Gliomas are classified based mainly on microscopic resemblance to their presumed glial origin such as astrocyte and oligodendrocyte. However, more objective diagnostic criteria are indispensable for the precise treatment of patients. For instance, loss of the short arm of chromosome 1 (1p) in oligodendrogliomas is recognized as an important marker for better response to chemotherapy and longer survival of the patients. To gain insight into their molecular biological background and to identify genes characterizing each subgroup, we investigated gene expression profile of the 4 glioma subsets, oligodendroglioma with and without 1p loss, diffuse astrocytoma and glioblastoma using DNA microarray. Remarkably, most of the genes showing distinctive expression in oligodendroglioma with 1p loss were also highly expressed in normal brain tissues and had neuron-related function, which included MYT1L, INA, RIMS2, SNAP97 and SNCB. Histological analysis also demonstrated that MYT1L, which were abundantly expressed in normal neuron, were certainly present in tumor cells. These results suggest that oligodendroglioma, especially with 1p loss, has more or less neuronal characteristics although oligodendroglioma is thought to originate form glial lineage cell. With further pathological studies, those neuron-related genes might be good diagnostic markers for oligodendroglioma of better prognosis as well.

Astrocytoma↗

PubMed2003

Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements.

Acute lymphoblastic leukemia (ALL) with 11q23 translocations is usually associated with MLL gene rearrangement, but little is known about its leukemogenesis. We analyzed the gene expression profiles of pediatric ALL samples according to their translocations. Using oligonucleotide microarray analysis, we identified distinct expression profiles for 23 ALL samples with 11q23 translocations, including t(4;11) (n = 15), t(11;19) (n = 6), and t(5;11) (n = 2), compared with 9 ALL samples with other translocations, including t(12;21) (n = 6) and t(1;19) (n = 3). Gene expression scores of FLT3, MeisI, and CD44 for samples with MLL rearrangements were particularly high compared with those for other ALL samples. Statistical analysis of the gene expression profiles for the 21 ALL samples with MLL rearrangements at diagnosis revealed two subgroups that exclusively correlated with prognosis but not with any other clinico-pathological factor. The transcription factors CBF2 and CDP were highly expressed in the poor and good prognosis subgroups, respectively. In addition, their downstream target genes were differentially expressed. These findings provide new insights into the biological mechanisms of leukemogenesis and prognosis for pediatric ALL with MLL rearrangements.

Child↗

PubMed2003

Reducing false positives in molecular pattern recognition.

In the search for new cancer subtypes by gene expression profiling, it is essential to avoid misclassifying samples of unknown subtypes as known ones. In this paper, we evaluated the false positive error rates of several classification algorithms through a 'null test' by presenting classifiers a large collection of independent samples that do not belong to any of the tumor types in the training dataset. The benchmark dataset is available at www2.genome.rcast.u-tokyo.ac.jp/pm/. We found that k-nearest neighbor (KNN) and support vector machine (SVM) have very high false positive error rates when fewer genes (<100) are used in prediction. The error rate can be partially reduced by including more genes. On the other hand, prototype matching (PM) method has a much lower false positive error rate. Such robustness can be achieved without loss of sensitivity by introducing suitable measures of prediction confidence. We also proposed a cluster-and-select technique to select genes for classification. The nonparametric Kruskal-Wallis H test is employed to select genes differentially expressed in multiple tumor types. To reduce the redundancy, we then divided these genes into clusters with similar expression patterns and selected a given number of genes from each cluster. The reliability of the new algorithm is tested on three public datasets.

Computational Biology↗

PubMed2002

Learning the parts of objects by auto-association.

Recognition-by-components is one of the possible strategies proposed for object recognition by the brain, but little is known about the low-level mechanism by which the parts of objects can be learned without a priori knowledge. Recent work by Lee and Seung (Nature 401 (1999) 788) shows the importance of non-negativity constraints in the building of such models. Here we propose a simple feedforward neural network that is able to learn the parts of objects by the auto-association of sensory stimuli. The network is trained to reproduce each input with only excitatory interactions. When applied to a database of facial images, the network extracts localized features that resemble intuitive notion of the parts of faces. This kind of localized, parts-based internal representation is very different from the holistic representation created by the unconstrained network, which emulates principal component analysis. Furthermore, the simple model has some ability to minimize the number of active hidden units for certain tasks and is robust when a mixture of different stimuli is presented.

Algorithms↗