Discovery of tissue-specific exons using comprehensive human exon microarrays

Clark, Tyson A.; Schweitzer, Anthony; Chen, Tina X.; Staples, Michelle K; Lü, Gang; Wang, Hui; Williams, Alan J.; Blume, John E.

doi:10.1186/gb-2007-8-4-r64

Cited by 261 publications

(324 citation statements)

References 50 publications

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“…Furthermore, the "Detection Above Background (DABG)" algorithm (Affymetrix Inc.) was used to identify signals within the background noise. Exon arrays tend to false-positive results (34), which can be reduced by EAA because of various filters (32). The most important filter exclude exons that are not expressed in both groups, genes that are not expressed in either groups, as well as probe sets that are known to cross-hybridize.…”

Section: Methodsmentioning

confidence: 99%

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1

Boeckel¹,

Guarani²,

Koyanagi³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

126

140

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JmjC domain-containing proteins play a crucial role in the control of gene expression by acting as protein hydroxylases or demethylases, thereby controlling histone methylation or splicing. Here, we demonstrate that silencing of Jumonji domain-containing protein 6 (Jmjd6) impairs angiogenic functions of endothelial cells by changing the gene expression and modulating the splicing of the VEGF-receptor 1 (Flt1). Reduction of Jmjd6 expression altered splicing of Flt1 and increased the levels of the soluble form of Flt1, which binds to VEGF and placental growth factor (PlGF) and thereby inhibits angiogenesis. Saturating VEGF or PlGF or neutralizing antibodies directed against soluble Flt1 rescued the angiogenic defects induced by Jmjd6 silencing. Jmjd6 interacts with the splicing factors U2AF65 that binds to Flt1 mRNA. In conclusion, Jmjd6 regulates the splicing of Flt1, thereby controlling angiogenic sprouting.

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Section: Methodsmentioning

confidence: 99%

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1

Boeckel¹,

Guarani²,

Koyanagi³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

126

140

View full text Add to dashboard Cite

show abstract

“…The rate of alternative splicing of mRNAs has been the focus of different studies and it seems that more than 60% of the human genes produce at least one alternative mRNA. 25 The functional implication of alternative splicing in normal and pathological states has been studied by several groups, 26,27 but there are still many questions to be answered. Future studies will be focused on the functional relevance of splice variants in the context of whole genome studies, instead of a single gene to understand how they will affect cellular networks and pathways.…”

Section: New Players In Pharmacogenomicsmentioning

confidence: 99%

The impact of microRNAs and alternative splicing in pharmacogenomics

2009

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“…2). Interestingly, the GenBank entries are previously unpublished RT-PCR validations of testis-specific exons, which were identified in a large-scale study by Clark et al (2007). Their study employed exon arrays to locate tissuespecific exons in 16 normal tissues, but focused on novel, brain-enriched exons in the published manuscript (Clark et al 2007).…”

Section: Identification and Cloning Of Novel Cryptic Exons Of The Ghmentioning

confidence: 99%

“…Interestingly, the GenBank entries are previously unpublished RT-PCR validations of testis-specific exons, which were identified in a large-scale study by Clark et al (2007). Their study employed exon arrays to locate tissuespecific exons in 16 normal tissues, but focused on novel, brain-enriched exons in the published manuscript (Clark et al 2007). To verify whether the novel exons correspond to splice variants of the ghrelin gene and to determine the open reading frame of these transcripts, RT-PCRs were performed (using cDNA reverse transcribed with oligo(dT) 18 primers) using RNA from the LNCaP prostate cancer cell line, human testis and pancreas (with a forward primer in exon 1 of ghrelin and a reverse primer in the novel exon II, which is common to all of the testis-derived GenBank entries).…”

Section: Identification and Cloning Of Novel Cryptic Exons Of The Ghmentioning

confidence: 99%

Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer

Seim¹,

Lubik²,

Lehman³

et al. 2012

Journal of Molecular Endocrinology

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Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homoeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 amino acid preproghrelin isoform that codes for ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia have been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate-resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products.

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Discovery of tissue-specific exons using comprehensive human exon microarrays

Abstract: Comprehensive exon microarrays with a simple intra-gene normalization algorithm were used to detect human tissue-specific alternative splicing events, suggesting significant expression outside of known exons and well annotated genes and a high frequency of alternative splicing events.

Cited by 261 publications

References 50 publications

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1

The impact of microRNAs and alternative splicing in pharmacogenomics

Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer

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