Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array

Gardina, Paul J.; Clark, Tyson A.; Shimada, Brian; Staples, Michelle K; Yang, Qing; Veitch, James; Schweitzer, Anthony; Awad, Tarif; Sugnet, Charles W.; Dee, Suzanne; Davies, Christopher; Williams, Alan J.; Turpaz, Yaron

doi:10.1186/1471-2164-7-325

Cited by 315 publications

(338 citation statements)

References 56 publications

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“…The exon array assesses the abundance of all exons from both empirically curated mRNA sequences and computationally predicted transcripts. In addition to gene level changes, the exon array can also reveal variations in individual exons that may result from alternative splicing, promoter utilization, termination, and polyadenylation (27)(28)(29). Principle component analysis indicates that the data points for NELF-A, -C, and -E knockdown cells were all clustered with each other and well separated from those of the control knockdown cells (supplemental Fig.…”

Section: Nelf-a -C and -E Knockdown Results In Reduced Expression Omentioning

confidence: 99%

Human Negative Elongation Factor Activates Transcription and Regulates Alternative Transcription Initiation

Sun

2010

Journal of Biological Chemistry

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The human negative elongation factor (NELF) is a four-subunit protein complex that inhibits the movement of RNA polymerase II (RNAPII) at an early elongation stage in vitro. NELFmediated stalling of RNAPII also attenuates transcription of a number of inducible genes in human cells. To obtain a genomewide understanding of human NELF-mediated transcriptional regulation in vivo, we carried out an exon array study in T47D breast cancer cells with transient small interfering RNA knockdown of individual NELF subunits. Upon depletion of NELF-A, -C, or -E, the vast majority of NELF-regulated genes were downregulated. Many of the down-regulated genes encode proteins that play key roles in cell cycle progression. Consequently, NELF knockdown resulted in significant reduction in DNA synthesis and cell proliferation. Chromatin immunoprecipitation showed that NELF knockdown led to dissociation of RNAPII from the promoter-proximal region of the cell cycle-regulating genes. This was accompanied by decreased histone modifications associated with active transcription initiation (H3K9Ac) and elongation (H3K36Me3), as well as reduced recruitment of the general transcription factor TFIIB and increased overall histone occupancy at a subset of the down-regulated promoters. Lastly, our study indicates that NELF regulates alternative transcription initiation of BSG (Basigin) gene by differentially influencing RNAPII density at the two neighboring exons at the 5 end of the gene. Taken together, our data suggest a diverse transcriptional consequence of NELF-mediated RNAPII pausing in the human genome.

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Section: Nelf-a -C and -E Knockdown Results In Reduced Expression Omentioning

confidence: 99%

Human Negative Elongation Factor Activates Transcription and Regulates Alternative Transcription Initiation

Sun

2010

Journal of Biological Chemistry

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“…Recently, studies have suggested that lncRNA expression profiling may be achieved by mining existing microarray data because some probes uniquely mapping to lncRNAs are fortuitously represented on these arrays [33,34] . The Affymetrix Human Exon 1.0 ST array consists of over 6.5 million individual probes designed along the entire length of the gene as opposed to just the 3' end, providing a unique platform for mining lncRNA profiles [35,36] . The lncRNA list used in this study was retrieved from Ensembl and is equivalent to the GENCODE lncRNA data set.…”

Section: Discussionmentioning

confidence: 99%

Analysis of long non-coding RNA expression profiles in gastric cancer

Cao

Wu²,

He³

et al. 2013

WJG

179

159

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AIM:To investigate the expression patterns of long non-coding RNAs (lncRNAs) in gastric cancer. METHODS:Two publicly available human exon arrays for gastric cancer and data for the corresponding normal tissue were downloaded from the Gene Expression Omnibus (GEO). We re-annotated the probes of the human exon arrays and retained the probes uniquely mapping to lncRNAs at the gene level. LncRNA expression profiles were generated by using robust multi-array average method in affymetrix power tools. The normalized data were then analyzed with a Bioconductor package linear models for microarray data and genes with adjusted P -values below 0.01 were considered differentially expressed. An independent data set was used to validate the results. RESULTS:With the computational pipeline established to re-annotate over 6.5 million probes of the Affymetrix Human Exon 1.0 ST array, we identified 136053 probes uniquely mapping to lncRNAs at the gene level. These probes correspond to 9294 lncRNAs, covering nearly 76% of the GENCODE lncRNA data set. By analyzing GSE27342 consisting of 80 paired gastric cancer and normal adjacent tissue samples, we identified 88 lncRNAs that were differentially expressed in gastric cancer, some of which have been reported to play a role in cancer, such as LINC00152, taurine upregulated 1, urothelial cancer associated 1, Pvt1 oncogene, small nucleolar RNA host gene 1 and LINC00261. In the validation data set GSE33335, 59% of these differentially expressed lncRNAs showed significant expression changes (adjusted P -value < 0.01) with the same direction. CONCLUSION:We identified a set of lncRNAs differentially expressed in gastric cancer, providing useful information for discovery of new biomarkers and therapeutic targets in gastric cancer. © 2013 Baishideng. All rights reserved.Key words: Long non-coding RNA; Gastric cancer; Microarray analysis; Data mining Core tip: Long non-coding RNAs (lncRNAs) have risen to prominence with important roles in a broad range of biological processes. LncRNA expression patterns and their biological functions in gastric cancer still remain unknown. We re-annotated the probes from an Affymetrix Human Exon 1.0 ST array and identified probes uniquely mapping to lncRNAs at the gene level. These probes correspond to 9294 lncRNAs, covering nearly 76% of the GENCODE lncRNA data set. We identified a set of lncRNAs that were differentially expressed in gastric cancer. In an independent data set, 59% of these differentially expressed lncRNAs showed significant expression changes with the same direction.

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“…These designs have facilitated analyses of genome-wide alternative splicing in human, mouse, and chimp (Srinivasan et al 2005;Boutz et al 2007;Calarco et al 2007;Ip et al 2007;Ni et al 2007), as well as detection of the global impact of specific splicing factors or environmental stimuli on splicing regulation (Park et al 2004;Hung et al 2007;Makeyev et al 2007;Pleiss et al 2007a,b). A very high-density ''exon array'' containing probes in essentially all known and predicted human exons was recently developed by Affymetrix (Gardina et al 2006). Generally speaking, these array platforms appear able to identify a subset of AS events with high confidence, but have an unknown and probably substantial rate of false negatives.…”

Section: Global Analyses Of Splicing Regulationmentioning

confidence: 99%

Splicing regulation: From a parts list of regulatory elements to an integrated splicing code

Wang¹,

Burge²

2008

RNA

887

761

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Alternative splicing of pre-mRNAs is a major contributor to both proteomic diversity and control of gene expression levels. Splicing is tightly regulated in different tissues and developmental stages, and its disruption can lead to a wide range of human diseases. An important long-term goal in the splicing field is to determine a set of rules or ''code'' for splicing that will enable prediction of the splicing pattern of any primary transcript from its sequence. Outside of the core splice site motifs, the bulk of the information required for splicing is thought to be contained in exonic and intronic cis-regulatory elements that function by recruitment of sequence-specific RNA-binding protein factors that either activate or repress the use of adjacent splice sites. Here, we summarize the current state of knowledge of splicing cis-regulatory elements and their context-dependent effects on splicing, emphasizing recent global/genome-wide studies and open questions.Keywords: context dependence; pre-mRNA splicing; splicing code; splicing factor; splicing regulation PRE-MRNA SPLICING Because human genes typically contain multiple introns, the process of pre-mRNA splicing is an essential step in the expression of most genes. A majority of human genes undergo alternative splicing (AS), generating multiple splicing isoforms containing different combinations of exons (Johnson et al. 2003). The effects of AS on protein products can be dramatic, e.g., producing soluble versus membranebound forms of the Fas receptor that have opposing effects on apoptosis (Cascino et al. 1995), or producing isoforms of the Drosophila fruitless protein that act to specify sexual orientation (Demir and Dickson 2005). The major forms of AS are summarized in Figure 1A. Splicing regulation has been comprehensively described in several recent reviews (Black 2003;Konarska and Query 2005;Matlin et al. 2005;Blencowe 2006;House and Lynch 2008). Here, we briefly summarize some aspects of splicing specificity and regulation before turning to our main topic of splicing regulatory elements and the rules governing their activity.The sequential phosphodiester transfer reactions involved in splicing are catalyzed by large ribonucleoprotein complexes known as spliceosomes. Containing more than 100 core proteins and five small nuclear RNAs (snRNAs U1, U2, U4, U5, and U6), spliceosomes may be the most complex machines in the cell (Zhou et al. 2002;Jurica and Moore 2003;Nilsen 2003). In addition to these core factors, additional regulatory proteins participate in the splicing of particular pre-mRNAs. Splicing of most introns is thought to occur cotranscriptionally with fairly extensive interactions between splicing factors and the core transcription machinery ( CORE SPLICING SIGNALSThree sites, the 59 splice site (59ss), the 39 splice site (39ss), and the branch point sequence (BPS), participate in the splicing reaction and are present in every intron, and thus are known as the core splicing signals. These signals are recognized multiple times during spl...

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Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array

Cited by 315 publications

References 56 publications

Human Negative Elongation Factor Activates Transcription and Regulates Alternative Transcription Initiation

Human Negative Elongation Factor Activates Transcription and Regulates Alternative Transcription Initiation

Analysis of long non-coding RNA expression profiles in gastric cancer

Splicing regulation: From a parts list of regulatory elements to an integrated splicing code

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