Intronic promoters and their noncoding transcripts: A new source of cancer‐associated genes

Relle, Manfred; Becker, Marc A.; Meyer, Ralf G.; Stassen, Michael; Schwarting, Andreas

doi:10.1002/mc.21955

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…~45% of promoters can be within intergenic regions, hinting a lot of potential protein or RNA genes unknown in the intergenic regions. Intronic promoters account for ~24%, consistent with the study that lots of latent noncoding RNA genes within introns [ 35 ]; Intronic promoters are associated with various disorders, including cancer [ 36 ]. Dr. Ingolia found pervasive translation outside of annotated protein-coding genes through ribosome profiling analysis, implying that a lot of transcription promoters are located outside of protein-coding genes [ 37 ].…”

Section: Resultssupporting

confidence: 72%

Disease-associated variants in different categories of disease located in distinct regulatory elements

Ren

Chuang

et al. 2015

BMC Genomics

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BackgroundThe invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression.ResultsIn this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects.We further found that regulatory regions are located within over 50% coding exon regions. Transcription promoters, methylation regions, and transcription insulators have the highest density of disease variants, with 472, 239, and 72 disease variants per one million base pairs, respectively.ConclusionsDisease-associated variants in different disease categories are preferentially located in particular regulatory elements. These results will be useful for an overall understanding about the differences among the pathogenic mechanisms of various disease-associated variants.

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Section: Resultssupporting

confidence: 72%

Disease-associated variants in different categories of disease located in distinct regulatory elements

Ren

Chuang

et al. 2015

BMC Genomics

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“…This led to a speculation that ATF4 could be binding to the intronic promoter of the TLR2 gene. Adding credence to this hypothesis are reports identifying an intronic promoter in the murine proteinase 3 gene [ 42 ] and another report that described the binding of ATF4 to an intronic promoter leading, in turn, to regulated expression of Siah2 mRNA in response to ER stress [ 43 ]. Interestingly, ATF4-binding site is also present in the first intron of the human VEGFA gene [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis

Liao

Guo

Niu

et al. 2016

J Neuroinflammation

103

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BackgroundNeuroinflammation associated with advanced human immunodeficiency virus (HIV)-1 infection is often exacerbated by chronic cocaine abuse. Cocaine exposure has been demonstrated to mediate up-regulation of inflammatory mediators in in vitro cultures of microglia. The molecular mechanisms involved in this process, however, remain poorly understood. In this study, we sought to explore the underlying signaling pathways involved in cocaine-mediated activation of microglial cells.MethodsBV2 microglial cells were exposed to cocaine and assessed for toll-like receptor (TLR2) expression by quantitative polymerase chain reaction (qPCR), western blot, flow cytometry, and immunofluorescence staining. The mRNA and protein levels of cytokines (TNFα, IL-6, MCP-1) were detected by qPCR and ELISA, respectively; level of reactive oxygen species (ROS) production was examined by the Image-iT LIVE Green ROS detection kit; activation of endoplasmic reticulum (ER)-stress pathways were detected by western blot. Chromatin immunoprecipitation (ChIP) assay was employed to discern the binding of activating transcription factor 4 (ATF4) with the TLR2 promoter. Immunoprecipitation followed by western blotting with tyrosine antibody was used to determine phosphorylation of TLR2. Cocaine-mediated up-regulation of TLR2 expression and microglial activation was validated in cocaine-injected mice.ResultsExposure of microglial cells to cocaine resulted in increased expression of TLR2 with a concomitant induction of microglial activation. Furthermore, this effect was mediated by NADPH oxidase-mediated rapid accumulation of ROS with downstream activation of the ER-stress pathways as evidenced by the fact that cocaine exposure led to up-regulation of pPERK/peIF2α/ATF4 and TLR2. The novel role of ATF4 in the regulation of TLR2 expression was confirmed using genetic and pharmacological approaches.ConclusionsxThe current study demonstrates that cocaine-mediated activation of microglia involves up-regulation of TLR2 through the ROS-ER stress-ATF4-TLR2 axis. Understanding the mechanism(s) involved in cocaine-mediated up-regulation of ROS-ER stress/TLR2 expression and microglial activation could have implications for the development of potential therapeutic targets aimed at resolving neuroinflammation in cocaine abusers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0501-2) contains supplementary material, which is available to authorized users.

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“…23,24 An intronic promoter was recently identified in murine Prtn3 that drives expression of an alternative mRNA initiated in intron 2 rather than intron 1. 25 Murine Prtn3 diverges from human PRTN3 gene and lacks the alternative promoter in intron 1 and an orthologous translational start codon in exon 2. Murine and human PR3 also differ in the amino acid sequence and biophysical properties.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Autoantigen Genes in ANCA-Associated Vasculitis Involves Alternative Transcripts and New Protein Synthesis

McInnis

Badhwar

Muthigi

et al. 2015

Journal of the American Society of Nephrology

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Proteinase 3 (PR3) and myeloperoxidase (MPO) are two major autoantigens in patients with vasculitis with ANCA. The genes encoding these autoantigens are abnormally expressed in peripheral granulocytes of patients with active ANCA-associated vasculitis. This study provides evidence that this transcriptional dysregulation results in a variety of mRNA processing events from the PRTN3 gene locus. In addition to elevated levels of PR3 message, leukocyte RNA from patients contained PR3 transcripts with an alternative 39 untranslated region. Furthermore, we detected usage of an alternative transcription start site within intron 1 of the PRTN3 gene locus that coincided with active disease (odds ratio, 3.3; 95% confidence interval, 1.3 to 8.4; P=0.01). This promoter may be developmentally regulated, because it was active in normal human bone marrow, multiple leukemia cell lines, MCF-7 cells, and subjects after GM-CSF treatment but not subjects with a neutrophil left shift. This transcript, which lacks exon 1 of PRTN3, encodes a 24-kD protein (p24 PR3/MBN ) with a sequence similar to that previously described for myeloblastin. Notably, PR3, p24 PR3/MBN , and MPO were synthesized in cultured neutrophils from patients with active ANCA-associated vasculitis, indicating that increased transcription results in newly synthesized autoantigens in peripheral neutrophils of patients. The synthesis of p24 PR3/MBN seems to expand the autoantigen repertoire, because immunoblots showed that sera from patients recognized p24 PR3/MBN .These findings emphasize the importance of transcriptional dysregulation of the autoantigen in autoimmune disease.

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Intronic promoters and their noncoding transcripts: A new source of cancer‐associated genes

Cited by 7 publications

References 35 publications

Disease-associated variants in different categories of disease located in distinct regulatory elements

Disease-associated variants in different categories of disease located in distinct regulatory elements

Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis

Dysregulation of Autoantigen Genes in ANCA-Associated Vasculitis Involves Alternative Transcripts and New Protein Synthesis

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