Academic literature on the topic 'Chimeric transcripts'
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Journal articles on the topic "Chimeric transcripts"
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Lalani, Samir, Sehajroop Gadh, Justin Elfman, Sandeep Singh, and Hui Li. "Abstract 4351: Differential dependency mapping of chimeric RNAs across cancer reveals a new landscape of functional fusion transcripts." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4351. http://dx.doi.org/10.1158/1538-7445.am2024-4351.
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Abstract Chimeric RNAs are RNA transcripts containing sequences originating from multiple distinct genetic loci and can form through a variety of mechanisms such as DNA rearrangement, cis-splicing of adjacent genes, or RNA trans-splicing. Chimeras have long been known to be a hallmark of cancer and due to their unique properties are promising targets for precision medicine. Appropriately, fusion proteins transcribed from chimeras such as BCR-ABL1 and TPM3-NTRK1 have been shown to be effective targets. Due to these past successes, there exists an opportunity to identify new chimeras as therapeutic targets. While modern chimera prediction software allows for the fast and accurate identification of chimeric RNAs from RNA sequencing data, investigations separating therapeutically relevant transcripts from “transcriptional noise” remain lacking. In this study we performed an in-silico functional screen of chimeras across cell lines representing a wide variety of cancers. We used state-of-the-art chimeric RNA prediction software to create a database of chimeric RNAs across 1017 cell lines from The Cancer Cell Line Encyclopedia. For each chimera we assessed factors such as frequency, recurrence, breakpoint coordinates, frame, and coding potential. To identify specific functional transcripts, we integrated publicly available shRNA knockdown data with our predictions and developed an in-silico functional analysis pipeline comparing differential knockdown effects between chimera and corresponding parental transcripts. For each transcript we assessed the average fold change of chimera-mapping probes, a function score defined as the difference between the fold change of chimera-mapping and parent-specific probes, and a p-value assessing the confidence of our functional score. From our initial screen of 127,819 transcripts, we identified 1088 high-confidence functional chimeras. We successfully identified nearly all known functional chimeras screened including PAX3-FOXO1, EWSR1-FLI1, and TCF3-PBX1. We also identified previously unknown chimeras that that we predict have a function in cell growth and proliferation. Overall, the results of our study reveal a new landscape of functionally relevant chimeric transcripts in cancer. Follow-up studies can further investigate these transcripts to determine their potential as therapeutic targets. Citation Format: Samir Lalani, Sehajroop Gadh, Justin Elfman, Sandeep Singh, Hui Li. Differential dependency mapping of chimeric RNAs across cancer reveals a new landscape of functional fusion transcripts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4351.
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Rowsell, Joanna, Renata da Silva Camargo, William B. Langdon, Maria A. Stalteri, and Andrew P. Harrison. "Uncovering the expression patterns of chimeric transcripts using surveys of Affymetrix GeneChips." Journal of Integrative Bioinformatics 7, no. 3 (December 1, 2010): 300–330. http://dx.doi.org/10.1515/jib-2010-137.
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Summary Background: A chimeric transcript is a single RNA sequence which results from the transcription of two adjacent genes. Recent studies estimate that at least 4% of tandem human gene pairs may form chimeric transcripts. Affymetrix GeneChip data are used to study the expression patterns of tens of thousands of genes and the probe sequences used in these microarrays can potentially map to exotic RNA sequences such as chimeras.Results: We have studied human chimeras and investigated their expression patterns using large surveys of Affymetrix microarray data obtained from the Gene Expression Omnibus. We show that for six probe sets, a unique probe mapping to a transcript produced by one of the adjacent genes can be used to identify the expression patterns of readthrough transcripts. Furthermore, unique probes mapping to an intergenic exon present only in the MASK-BP3 chimera can be used directly to study the expression levels of this transcript.Conclusions: We have attempted to implement a new method for identifying tandem chimerism. In this analysis unambiguous probes are needed to measure run-off transcription and probes that map to intergenic exons are particularly valuable for identifying the expression of chimeras.
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Amundarain, Ane, Luis Vitores Valcárcel, Raquel Ordoñez, Leire Garate, Estíbaliz Miranda, Xabier Cendoya, Maria Jose Calasanz, et al. "Lncrnas As New Partners of Novel Chimeric Transcripts in Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 4356. http://dx.doi.org/10.1182/blood-2019-122568.
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Deregulation of long non-coding RNAs (lncRNAs) is a common feature of cancer, including Multiple Myeloma (MM). In our previous studies, we detected 11,495 and 40,511 previously non-annotated lncRNAs during normal humoral immune response and MM patient samples, respectively. These results support an important role for the lncRNAs transcriptome in this hematological malignancy. lncRNAs are genes that differ from coding genes in that they do not give rise to a protein. Nevertheless, lncRNA could undergo the same genetic alterations as coding genes. In this study, we hypothesize that lncRNAs can be involved in the principal genetic alterations occurring in MM such as chromosomal translocations, affecting the Immunoglobulin loci (IG) and in the majority of which the fusion partner still remains unknown. In order to unveil the role of lncRNAs in fusion transcripts occurring in MM, we analyzed the strand specific RNA-seq (ssRNA-seq) data obtained from 35 samples from different subpopulations of B cells (Naïve, Centroblast, Centrocyte, Memory and Plasma cells (PCs)), purified PCs from 32 MM patients and 3 MM cell lines. Chimeric transcripts were detected with the STAR-Fusion software, identifying 1,347 novel fusion transcripts ranging from 1 to 142 chimeric transcripts per sample. Strikingly, healthy PC samples (from tonsils and bone marrow) yielded the highest number of fusion transcripts, while other B cell subpopulations showed overall low numbers and MM samples turned out highly variable. 96% of all fusion transcripts detected in healthy PCs occurred with IG genes and harbored few reads per transcript, suggesting that the hyperactive transcription of the IG loci in PCs may be the cause for their formation and are probably not involved in the pathogenesis of the disease. We also found that HLA fusion transcripts were abundant in Naïve B cells, disappearing progressively during the humoral immune response (Figure 1). Interestingly, fusion transcripts identified in different B cell subpopulations were not detected in MM samples. Next, we focus on myeloma samples and identified 362 chimeric transcripts (312 unique) expressed specifically in MM (ranging from 2 to 24 chimeric transcripts per sample), most of them (84%) identified for the first time. 69% of these transcripts partnered with the IG genes, while the other fusions involved two non-IG genes. Interestingly, as we hypothesized, 26,5% of the chimeric transcripts in MM occurred with lncRNA as a partner, increasing the relevance of lncRNAs in this disease. Furthermore, using the read distribution per chimeric transcript, we identified a prevalent reciprocal transcript or a prevalent transcript expressed with >1 FFPM in 47% of MM samples, suggesting that they could derived from underlying genomic rearrangements. Besides these prevalent transcripts, we observed that 40% of the non-IG fusion transcripts occurred between adjacent genes, defining novel MM-transcriptional read-throughs, possibly caused by the oncogenic stress suffered by MM cells. Some of these chimeric transcripts were validated in different cell lines of MM by conventional PCR and sequencing. In summary, our findings show that ssRNA-seq data is an adequate strategy for the detection of chimeric transcripts in MM, being able to detect highly expressed chimeric transcripts that probably were derived from an underlying genomic rearrangements and also new categories of chimeric transcripts. In addition, our study reveals a complex landscape of fusion transcripts in the MM, many of them including a lncRNA, which could be potential therapeutic targets for the development of new treatment strategies for MM. Disclosures Paiva: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.
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Alterman, R. B., C. Sprecher, R. Graves, W. F. Marzluff, and A. I. Skoultchi. "Regulated expression of a chimeric histone gene introduced into mouse fibroblasts." Molecular and Cellular Biology 5, no. 9 (September 1985): 2316–24. http://dx.doi.org/10.1128/mcb.5.9.2316-2324.1985.
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The regulated expression of a mouse histone gene was studied by DNA-mediated gene transfer. A chimeric H3 histone gene was constructed by fusing the 5' and 3' portions of two different mouse H3 histone genes. Transfection of the chimeric gene into mouse fibroblasts resulted in the production of chimeric mRNA at levels nearly equal to that of the total endogenous H3 histone mRNAs. Most chimeric RNA transcripts had correct 5' and 3' termini, and the chimeric mRNA was translated into an H3.1 protein that accumulated in the nucleus of the transfected cells. Expression of the chimeric gene was studied under several conditions in which the rate of transcription and the stability of endogenous H3 transcripts change. Chimeric mRNA levels were regulated in parallel with endogenous H3 mRNAs, suggesting that cis-acting regulatory sequences lie within or near individual histone genes. In addition to correctly initiated and terminated chimeric mRNA, we also detected a novel H3 transcript containing an additional 250 bases at the 3' end. Surprisingly, the longer transcript is polyadenylated and accumulates in the cytoplasm.
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Alterman, R. B., C. Sprecher, R. Graves, W. F. Marzluff, and A. I. Skoultchi. "Regulated expression of a chimeric histone gene introduced into mouse fibroblasts." Molecular and Cellular Biology 5, no. 9 (September 1985): 2316–24. http://dx.doi.org/10.1128/mcb.5.9.2316.
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The regulated expression of a mouse histone gene was studied by DNA-mediated gene transfer. A chimeric H3 histone gene was constructed by fusing the 5' and 3' portions of two different mouse H3 histone genes. Transfection of the chimeric gene into mouse fibroblasts resulted in the production of chimeric mRNA at levels nearly equal to that of the total endogenous H3 histone mRNAs. Most chimeric RNA transcripts had correct 5' and 3' termini, and the chimeric mRNA was translated into an H3.1 protein that accumulated in the nucleus of the transfected cells. Expression of the chimeric gene was studied under several conditions in which the rate of transcription and the stability of endogenous H3 transcripts change. Chimeric mRNA levels were regulated in parallel with endogenous H3 mRNAs, suggesting that cis-acting regulatory sequences lie within or near individual histone genes. In addition to correctly initiated and terminated chimeric mRNA, we also detected a novel H3 transcript containing an additional 250 bases at the 3' end. Surprisingly, the longer transcript is polyadenylated and accumulates in the cytoplasm.
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Claxton, DF, P. Liu, HB Hsu, P. Marlton, J. Hester, F. Collins, AB Deisseroth, JD Rowley, and MJ Siciliano. "Detection of fusion transcripts generated by the inversion 16 chromosome in acute myelogenous leukemia." Blood 83, no. 7 (April 1, 1994): 1750–56. http://dx.doi.org/10.1182/blood.v83.7.1750.1750.
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Abstract Pericentric inversion of chromosome 16 [inv(16)(p13q22)] and the related t(16;16)(p13;q22) are seen in a subset of acute myelogenous leukemia (AML) phenotypically and prognostically differing from other cases. We have recently shown that inv(16) results in fusion of CBFB/PEBP2B, a gene encoded at 16q22 to MYH11, a smooth muscle myosin heavy chain gene encoded at 16p13. Chimeric transcripts consisting of upstream CBFB fused to downstream MYH11 coding sequences result from this fusion. In this study we have examined a series of 37 of these cases using reverse transcriptase-polymerase chain reaction (RT-PCR) to detect expression of a hybrid CBFB/MYH11 transcript. Chimeric cDNAs were detected in all but 1 of 37 leukemias with typical inv(16) or t(16;16). Such chimeric products were not seen in a case with inv(16)(p13q24) (ie, a variant q arm breakpoint) or any of 10 cases of AML without these chromosomal changes. Four different chimeric transcripts were found, representing differing fusion points within MYH11 spliced to position 495 of CBFB. Primer sets are described for efficient amplification of these different cDNA forms. Amplification of cDNA showed that all but 17 codons of the CBFB coding sequence are included in the abnormal transcripts. RT-PCR was shown to be highly sensitive and potentially useful for detection of leukemic cells during morphologic remission.
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Claxton, DF, P. Liu, HB Hsu, P. Marlton, J. Hester, F. Collins, AB Deisseroth, JD Rowley, and MJ Siciliano. "Detection of fusion transcripts generated by the inversion 16 chromosome in acute myelogenous leukemia." Blood 83, no. 7 (April 1, 1994): 1750–56. http://dx.doi.org/10.1182/blood.v83.7.1750.bloodjournal8371750.
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Pericentric inversion of chromosome 16 [inv(16)(p13q22)] and the related t(16;16)(p13;q22) are seen in a subset of acute myelogenous leukemia (AML) phenotypically and prognostically differing from other cases. We have recently shown that inv(16) results in fusion of CBFB/PEBP2B, a gene encoded at 16q22 to MYH11, a smooth muscle myosin heavy chain gene encoded at 16p13. Chimeric transcripts consisting of upstream CBFB fused to downstream MYH11 coding sequences result from this fusion. In this study we have examined a series of 37 of these cases using reverse transcriptase-polymerase chain reaction (RT-PCR) to detect expression of a hybrid CBFB/MYH11 transcript. Chimeric cDNAs were detected in all but 1 of 37 leukemias with typical inv(16) or t(16;16). Such chimeric products were not seen in a case with inv(16)(p13q24) (ie, a variant q arm breakpoint) or any of 10 cases of AML without these chromosomal changes. Four different chimeric transcripts were found, representing differing fusion points within MYH11 spliced to position 495 of CBFB. Primer sets are described for efficient amplification of these different cDNA forms. Amplification of cDNA showed that all but 17 codons of the CBFB coding sequence are included in the abnormal transcripts. RT-PCR was shown to be highly sensitive and potentially useful for detection of leukemic cells during morphologic remission.
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Fujieda, S., Y. Q. Lin, A. Saxon, and K. Zhang. "Multiple types of chimeric germ-line Ig heavy chain transcripts in human B cells: evidence for trans-splicing of human Ig RNA." Journal of Immunology 157, no. 8 (October 15, 1996): 3450–59. http://dx.doi.org/10.4049/jimmunol.157.8.3450.
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Abstract Germ-line transcripts from Ig heavy chain loci precede the occurrence of isotype switching and are thought to play an important though still controversial role in Ig class switching. In this study, we employed a reverse transcriptase-PCR approach to detect human chimeric Ig germ-line mRNA transcripts. Multiple types of chimeric Ig germ-line transcripts (Imu-Cepsilon, Iepsilon-Cmu, Imu-Cgamma4, Igamma-Cmu, Igamma-Cepsilon, Iepsilon-Cgamma, and Igamma4-Calpha1 transcripts) were readily detected in human B cells stimulated with IL-4 alone. Sequence analysis revealed that all of these chimeric Ig germ-line transcripts represented the I exons from one Ig locus spliced to the CH exons from another locus by using consensus sequences for splicing donor and acceptor sites, indicating that they were generated through splicing machinery. In the case of stimulation of human resting B cells with IL-4 alone, the chimeric Ig germ-line transcripts are likely derived from a trans-splicing mechanism, as the extensive searching did not find evidence that Ig class-switch recombination had occurred, which alternatively could give rise to chimeric Ig mRNA by mechanisms other than trans-splicing. Similarly, an EBV-transformed gamma2 rearranged B cell line, GM1500, which produces IgG2 and contains both gamma2 productive and epsilon germ-line transcripts, also expressed chimeric germ-line RNA (Iepsilon-Cgamma2) and epsilon-productive transcripts (VDJ-Cepsilon). This line had no further sequential Sgamma2-Sepsilon rearrangements, providing evidence that the productive VDJ-Cepsilon mRNA was derived from a transcriptionally active unrearranged epsilon gene locus by trans-splicing. Taken together, these results provide possible evidence that trans-splicing of germ-line Ig RNA transcripts occurs in human B cells.
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Zoubek, A., B. Dockhorn-Dworniczak, O. Delattre, H. Christiansen, F. Niggli, I. Gatterer-Menz, T. L. Smith, H. Jürgens, H. Gadner, and H. Kovar. "Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients?" Journal of Clinical Oncology 14, no. 4 (April 1996): 1245–51. http://dx.doi.org/10.1200/jco.1996.14.4.1245.
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PURPOSE Because of the high heterogeneity of EWS gene fusions with FLI1 and ERG genes due to variable chromosomal breakpoint locations in Ewing tumors (ET) (14 different chimeric transcripts identified so far), we evaluated the clinical impact of the expression of diverse fusion transcripts in ET patients. PATIENTS AND METHODS In a European multicenter study, 147 ET were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) and the molecular data statistically compared with all clinical data available. RESULTS Most tumors expressed chimeric transcripts with fusion of EWS exon 7 to FLI1 exon 6 (75 of 147) (type I) or five (39 of 147) and EWS exon 10 to FLI1 exon 5 (eight of 147) or 6 (five of 147). In five cases, chimerism between EWS exon 9 and FLI1 exons 4 and EWS exon 7 and FLI1 exon 7 or 8 was observed. Fifteen cases of EWS-ERG rearrangement were identified. In 85 of these patients treated in the European Cooperative Ewing Sarcoma Studies, molecular results were analyzed in comparison to age, sex, tumor localization, tumor volume, and disease extension. No significant correlation between the various fusion types and these features were observed. Relapse-free survival (RFS) for the 31 patients with localized disease and fusion type I tended to be longer compared with the 24 patients with localized tumors bearing other chimeric transcripts (P = .04). CONCLUSION Results suggest a possible advantage in PFS for patients with localized disease and fusion type I transcripts, although this will require prospective validation with a larger number of patients and longer follow-up periods.
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Katsuya, Hiroo, Paola Miyazato, Saiful Islam, Benjy Jek Yang Tan, Yuki Inada, Misaki Matsuo, Takaharu Ueno, et al. "The Presence and Possible Role of Virus-Host Chimeric Transcripts in Adult T-Cell Leukemia-Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 2779. http://dx.doi.org/10.1182/blood-2019-124361.
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The retrovirus human T-cell leukemia virus type 1 (HTLV-1) integrates into the host genome and persists for the lifetime of the host. There are tens of thousands of different infected clones in a HTLV-1 carrier and each clone can be identified by its unique viral integration site. Only about 5% of infected people develop the hematological malignancy, adult T-cell leukemia-lymphoma (ATL). However, it is unclear how a certain infected clone, among various different ones, is selected as a malignant clone. It has been reported that viral integration alters transcripts of the cellular host genes adjacent to the integration site, even generating truncated or virus-host chimeric transcripts. Because each infected clone has a unique viral integration site, each clone possibly has unique virus-host chimeric transcripts, which were not present in the host before infection. Therefore, we hypothesized that the integrated provirus generates virus-host chimeric transcripts that may play a role in the clonal selection of the HTLV-1-infected cell. We previously reported HTLV-1 DNA-capture-seq using biotinylated DNA-probes for the viral genome, to increase the sensitivity and efficiency of viral-sequences detection. In this study, we used HTLV-1 RNA-capture-seq for PBMCs samples from ATL patients to test the hypothesis in a highly sensitive manner. The results showed the presence of chimeric transcripts in 19 out of 30 ATL patients. We next quantified the abundance of chimeric transcripts by droplet digital PCR, and found that the expression levels of chimeric transcripts were similar to those of viral RNAs containing splice junction of HBZ, in 5 of 19 chimeric transcripts positive ATL cases, although the levels varied among different ATL cases. To identify the whole sequences of the chimeric transcripts, we performed Oxford Nanopore sequencing. This approach revealed that the HTLV-1 provirus generates various splicing chimeric transcripts with the host genes in both viral sense and antisense orientations. The transcriptional start site of most of the sense chimeric transcripts was the R region of the 5'- or 3'-long terminal repeats (LTRs) in the proviral sequences, indicating that the chimeric transcripts were generated using the viral promoters because the LTRs work as a promoter for the viral transcripts. Given the structure of the chimeric transcripts with the viral promotors, the expression of the fused host genes could be enhanced by generating the chimeric transcripts. We evaluated the mRNA expression of the fused host genes of the chimeric transcripts by RNA-seq, and the results correlated with those obtained by ddPCR. To clarify the impact of viral integration on the clonal expansion, we analyzed HTLV-1-infected Jurkat cells. The clonality analysis of infected cells by HTLV-1 DNA-capture-seq showed that some infected clones were remarkably expanded for 4-6 months culture. We also confirmed that some of them harbored virus-host chimeric transcripts by HTLV-1 RNA-capture-seq. This study revealed the expression levels and the structures of virus-host chimeric transcripts in ATL patients. We are currently investigating the functional role of chimeric transcripts in the clonal proliferation of infected cells in vitro. Disclosures Uchimaru: Daiichi Sankyo Co., Ltd..: Research Funding. Kimura:Novartis: Honoraria, Research Funding; Ohara Pharmaceutical Co.: Research Funding.
Dissertations / Theses on the topic "Chimeric transcripts"
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Xu, Hang. "Investigating the activity of L1 chimeric transcripts in human cancer." Thesis, University of Nottingham, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718854.
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Transposable elements (TEs) are repetitive sequences that occupy 45% to 65% of the human genome. TEs can transfer themselves to different locations in a host genome and they have had a considerable impact on the structural and functional evolution of genomes and transcriptomes. TE mobilisation activity can have deleterious consequences and de novo insertions have been implicated in genetic disorders, and acquired diseases such as cancer. A variety of mechanisms have evolved to prevent TE mobilisation in somatic cells spanning from epigenetic mechanisms that prevent transcription from TE promoters to the removal of TE RNAs. Activation of TE promoters also has consequences that are independent of mobilisation and has been reported to be responsible for increasing transcript diversity and rewiring of gene regulatory networks. A large portion of human RNA transcripts initiate within TEs with resulting changes in expression of surrounding protein-coding genes. A typical example is the long interspersed nuclear element (LINE-1 or LI) family of TEs. Aberrant transcription from LI promoters can result in LI chimeric transcripts (LCTs) which contain part of LI coupled to a unique genomic sequence. Recent evidence has suggested a causal link between certain LCTs and tumour progression, indicating their potential role in the development of cancer. The advances in high-throughput sequencing technologies provide us the opportunity to investigate the activity of LCTs on a genome-wide scale. However, one of the difficulties in genome-wide LCTs study is the lack of bioinformatic tools for repetitive elements involving chimeric transcript detection. Multiple computational tools have been produced to identify chimeric transcripts, however, most of them discard sequences that contain TEs because of their repetitive nature. The evidence that the activity of TEs may play a role in the control of gene networks encourages the development of new approaches to look into the transcriptome datasets. Establishing a relationship between expression of a given TE and expression of an adjacent or nearby gene may give a new insight in the study of TEs. In this study, I developed a novel computational tool - TECDetec (TE Chimeric Transcripts Detector) - which implements a strategy specialised for identifying and mapping chimeric transcripts associated with TEs, using transcriptome profiling obtained by paired-end RNA-Seq. The activity of LCTs was then studied using TECDetec in colorectal cancer patients and cell lines as well as in breast cancer cell lines. 22 LCTs which may relate to the tumour progression in CRC were highlighted. The enrichment of LCTs in nucleus but not in cytoplasm was observed, which suggested that the activity of LCTs in the human genome may be underestimated.
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Thomson, Gabrielle Anne Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Retroelements as controlling elements in mammals." Awarded by:University of New South Wales. Biotechnology and Biomolecular Sciences, 2006. http://handle.unsw.edu.au/1959.4/26203.
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Retroelements are genomic parasites which make up ~42% of the human genome and 38% of the mouse genome. Most are degenerate, but a large number have relatively intact promoter elements, suggesting that they are capable of transcription. Transcriptionally active retroelements can perturb normal transcription units in their vicinity through a variety of mechanisms, leading to phenotypic effects and in some cases disease. This phenomenon of transcriptional interference has been observed in organisms as diverse as maize, Drosophila, and the mouse. We analysed the extent of retroelement transcription in normal and diseased tissues, by searching the mouse and human EST databases for transcripts originating in retroelement promoters, and found a large number of transcripts from LINEs, SINEs and ERVs. Retroelement transcripts were found to be initiated in both sense and antisense orientations, and to be equally as common in normal and diseased tissue. Several of these transcripts were chimeric, appearing to initiate in retroelements and reading through to cellular genes, suggestive of transcriptional interference. We have used transposon display to identify and recover retroelement transcripts in the mouse. Transcripts initiated in LINE, SINE and ERV promoters are numerous, and many are chimeric with cellular genes. Although the numbers of recovered chimeric transcripts are too large to permit rigorous analysis of more than a small proportion, some of those we have studied further appear to be authentic transcripts that may represent interference with the canonical promoters of the genes in question. Our results suggest that transcriptional interference by retroelements may be a relatively common occurrence in mammals.
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Herai, Roberto Hirochi. "Metodologias de bioinformatica para detecção e estudo de sequencias repetitivas em loci genicos de transcritos quimericos." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317152.
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Orientador: Michel Eduardo Beleza YamagishiTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-15T17:21:19Z (GMT). No. of bitstreams: 1 Herai_RobertoHirochi_D.pdf: 3625854 bytes, checksum: 3f19d10a9b0bb7f77091197cd302f66e (MD5) Previous issue date: 2010
Resumo: A grande quantidade de dados biológicos gerados recentemente permitiu verificar que os genomas são repletos de seqüências repetitivas (SR), como microsatélites e elementos genéticos móveis, altamente improváveis de ocorrer estatisticamente se os genomas fossem gerados a partir de uma distribuição aleatória de nucleotídeos. Tal comprovação motivou a classificação de tais seqüências e também a construção de diversas ferramentas de bioinformática, além de mecanismos de armazenamento baseados em sistemas de gerenciamento de bancos de dados (SGBD) para permitir localizá-las e armazená-las para posterior estudo. Entretanto, foi com a comprovação biológica da importância das SR, como no mecanismo de interferência por RNAi (SR reversa complementar), que as SR despertaram maior interesse por parte da comunidade científica. Atualmente, já há fortes evidências que associam as SR com fenômenos biológicos bastante interessantes, como o processamento de RNA por cis-splicing e a formação de transcritos quiméricos, freqüentes em organismos inferiores e muito raro em organismos superiores. Tais tipos de transcritos podem ser gerados a partir de trans-splicing ou, como conjecturamos nesse trabalho, pela transposição de elementos genéticos móveis (como por exemplo transposons ou retrotransposons). Em virtude disso, este projeto propõe a construção de metodologias de Bioinformática, disponibilizadas na WEB, para detectar transcritos quiméricos em genomas de organismos, tanto em versões draft ou em alta qualidade, e também estudar as SR que ocorrem no locus gênico dos transcritos envolvidos na formação de uma seqüência quimérica. As ferramentas propostas permitiram identificar, a partir de bibliotecas de transcritos de full-length cDNA, tanto de humanos quanto de bovinos, novos transcritos quiméricos provenientes de células de tecidos normais, e que não seguem splice-sites canônicos na região de fusão dos transcritos envolvidos. Além disso, as seqüências encontradas apresentam uma elevada taxa de concentração de pares de SR do tipo reverso complementar no locus gênico dos dois transcritos que formam a seqüência quimérica. As ferramentas propostas podem ser utilizadas para outros organismos e direcionar trabalhos experimentais para tentar comprovar em bancada novos transcritos quiméricos, tanto em organismos inferiores quanto em superiores
Abstract: The recent availability of a huge amount of biological data allowed to know about the high concentration of repetitive sequences (SR) like microsatellites and genetic mobile elements in different genomes. Repetitive sequences are improbable to occur statistically if genome data were generated by a random distribution of nucleotides. Such observation motivated the classification of repetitive sequences, and the construction of several bioinformatics tools. Furthermore, several mechanisms to store repetitive sequences, which are based on data base management systems (DBMS) were proposed and created. They can be used to search for specific sequences to make a posteriori study. However, it was with the biological confirmation of the importance of repetitive sequences, like by the RNA interference (reverse complement, or inverted repeat) mechanism, that the scientific community gained more interest by such sequences. Actually, there is strong evidence that associates the repetitive sequences with some interesting biological phenomena, like in RNA processing by cis-splicing, and in chimeric transcript formation mechanism. This last one is very frequently in inferior organism, but rare in superior organisms. Such types of transcripts can be generated by trans-splicing, or like conjectured in this work, by the retrotransposition of mobile genetic elements (like transposons or retrotransposons). In this way, this work proposed the construction of several Bioinformatics methodologies, available in the WEB, to detect new evidences of chimeric transcripts in genomes of different organisms, both in draft genome and in high quality genome assemblage. We also studied repetitive sequences in gene loci of the involved transcripts in a chimeric sequence formation. The proposed tools allowed us to identify, using a full-length cDNA databank, new chimeric transcript candidates in human and in bovine genome. They are from cells of normal tissues, and do not follow canonical splice-sites in the fusion region of the involved transcripts. Moreover, it was possible to show that the detected sequences have high concentration pairs of reverse complement type of repetitive sequences in gene loci of the two involved transcripts, which originated a new chimeric transcript candidate. The created bioinformatics tools can be used in other organisms in addition to the one used in this work, leading to the proposition of new experimental work to try to prove in vivo new chimeric transcripts, both in superior organism and in inferior organism
Doutorado
Bioinformatica
Doutor em Genetica e Biologia Molecular
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Pinson, Marie-Elisa. "Etude de l'impact de la dérégulation transcriptionnelle liée à des transcrits chimères initiés à partir d'éléments répétés de type LINE-1 dans la tumorigenèse gliale." Thesis, Université Clermont Auvergne (2017-2020), 2017. http://www.theses.fr/2017CLFAS006/document.
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Les éléments LINE-1 (L1) sont une classe abondante de rétrotransposons représentant 17% du génome humain. La région 5’UTR des sous-familles les plus récentes (L1PA1 à 6) contient un promoteur bidirectionnel contenant non seulement un promoteur sens interne mais aussi un promoteur antisens, nommé ASP. Dans les cellules normales, l’un des mécanismes impliqués dans la régulation du promoteur de L1 est la méthylation ADN. Dans les tumeurs, une hypométhylation globale affectant notamment les L1 est observée. Il a été mis en évidence que cette hypométhylation pouvait induire la transcription, à partir de l’ASP, de transcrits chimères ou LCT (L1 Chimeric Transcript). Ces LCT sont composés en 5’ de la séquence L1 et se poursuivent dans la région génomique adjacente. Afin d’étudier l’impact pangénomique de cette dérégulation et son implication dans les processus tumoraux, un outil bio-informatique dédié, nommé CLIFinder, a été développé pour identifier dans des données de RNA-seq paired-end orientés des LCT putatifs. Les RNA-seq de 13 gliomes, qui sont les cancers du cerveau les plus fréquents chez l’adulte, et de 3 tissus cérébraux contrôles ont été étudiés. CLIFinder identifie 2675 chimères dans les gliomes dont 84% impliquent des L1 récents (PA1 à 7) pleine taille supposés posséder un ASP fonctionnel et 50% sont détectées spécifiquement dans les échantillons tumoraux. 78 chimères correspondent à des LCT déjà décrits dans la littérature. De même, l’étude de RNA-seq d’autres types tumoraux (lignée MCF7 et métastases ovariennes) par CLIFinder identifie des chimères en commun suggérant une récurrence de certaines d’entre elles. L’étude d’un groupe de chimères par marche en 5’ par RT-PCR valide que 89% (56/63) des chimères impliquant des L1 récents (L1PA1 à PA7) sont initiées dans la région de l’ASP et correspondent à des LCT alors que toutes les chimères testées impliquant des L1PA8 sont initiées en amont de cette région. Des études de RT-qPCR sur une cohorte plus large de 51 gliomes montrent que les 56 LCT testés, incluant des LCT spécifiques de tumeurs, sont exprimés non seulement dans les tumeurs mais aussi dans les contrôles. Par contre, 70% des LCT spécifiques de tumeurs, montrent alors une surexpression tumorale significative. Ces résultats suggèrent donc une transcription basale provenant de l’ASP dans les tissus normaux et que la dérégulation transcriptionnelle liées aux LCT dans les gliomes passe par une surexpression. Par ailleurs, afin de déterminer le ou les mécanismes sous-jacents impliqués dans l’augmentation de l’activité transcriptionnelle de l’ASP, deux hypothèses ont été testées. La première implique l’hypométhylation du promoteur de L1. Toutefois mes résultats tendent à réfuter cette hypothèse puisqu’aucune diminution de la méthylation ADN n’est retrouvée au niveau de la région promotrice des L1 impliqués dans la transcription de LCT surexprimés. Par contre, les gènes associés à des LCT dont l’expression est dérégulée en contexte tumoral présentent une dérégulation dans le même sens que celle du LCT. De plus, les variations d’expression de gènes corrèlent systématiquement avec celle des LCT correspondants. Ceci suggère qu’une augmentation d’activité transcriptionnelle aux loci des LCT serait responsable de la surexpression de ceux-ci. Enfin 2 LCT candidats surexprimés et ayant un potentiel de biomarqueur prédictif de la survie des patients, pourraient jouer un rôle fonctionnel dans l’initiation, la progression et/ou l’agressivité tumorale. En conclusion, mes travaux ont validé que CLIFinder se positionne comme un outil pertinent permettant d’identifier, de façon pangénomique, les LCT exprimés dans différents types tumoraux à partir de données de RNA-seq paired-end orientées. L’observation d’une récurrence ainsi que d’une surexpression tumorale de certains LCT suggère qu’ils pourraient jouer un rôle fonctionnel dans les processus de tumorigenèseLINE-1 (L1) is the most abundant class of retrotransposons which represents 17% of the human genome. The 5’ region of the youngest L1 sub-families (L1PA1 to 6) contains a bidirectional promoter consisting, in addition to the internal sense promoter, of an antisense promoter, called ASP. In normal cells, the main defense mechanism, developed to counteract the deleterious effect of L1 activity, consists in L1 promoter DNA methylation. A hallmark of cancer genomes consists in a global DNA hypomethylation which affects especially L1 promoters. In tumors, evidences suggest that this hypomethylation could result in transcription from ASP of aberrant L1-Chimeric Transcripts (LCTs) composed of L1 5’end and its adjacent sequence. To investigate the pangenomic extent of this transcriptional deregulation and its impact in tumoral processes, a dedicated bioinformatic tool, CLIFinder, was designed to select putative LCTs among RNA-seq oriented paired-end reads. RNA-seq analyses of 13 gliomas, which are the most common brain cancer in adults, and 3 control brains were performed.CLIFinder identifies 2675 chimeras in gliomas, among which 84% involves recent L1 (PA1 to 7) full size, supposed to possess a functional ASP, and 50% are detected specifically in tumors samples. 78 chimeras correspond to LCT already described in literature. In addition, study of additional RNA-seq data from other tumor types (MCF7 and ovarian metastasis) by CLIFinder identifies common chimeras suggesting that some of them can be recurrent. The analysis of a group of chimeras by 5’ walk RT-PCR validate that 89% (56/63) of chimeras implying recent L1 (L1PA1 to 7) are initiated at the ASP region and therefore correspond to LCT; whereas all tested chimeras implying an L1PA8 element are transcribed from an upstream region. RT-qPCR studies on a larger cohort of 51 gliomas show that all 56 tested LCT, even identified by CLIFinder as “tumor specific”, are not only expressed in tumors but also in controls. Nevertheless, 70% of the “tumor specific” LCTs are significantly overexpressed in tumors. My results suggest that, even L1 5’ UTR methylation, some ASP are active in normal tissues and lead to a basal LCT expression in normal tissues. Moreover, a transcriptional deregulation linked to LCTs in tumors exists and implies a LCTs’ overexpression.In order to determine the underlying mechanisms involved in the increase of transcriptional activity of ASP, two hypothesis were tested. The first one implies L1 promoter hypomethylation. My results tend to refute this hypothesis because no decrease of the DNA methylation is found at the promoter region of L1 linked to overexpressed LCTs. On the other hand, the genes associated to LCT presenting an expression deregulation in tumors demonstrate a deregulation in the same way. Moreover, gene expression variations correlates systematically with the one corresponding LCTs. This suggests that an increase of transcriptional activity at the LCTs loci would be responsible of their overexpression. Finally, 2 candidate LCT overexpressed and presenting as potential predictive biomarkers for patient’s survival, could play a functional role in initiation, progression and/or the tumoral aggressiveness.In conclusion, my work has validated CLIFinder as a useful tool to identify, at pangenomic level, LCTs expressed in different tumor types from paired-end stranded RNA-seq data. The observation of the recurrence and tumoral overexpression for some LCTs suggests that they may play a functional role in tumoral processes
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Mir, Ashfaq Ali. "Variations structurales du génome et du transcriptome humains induites par les rétrotransposons LINE-1." Thesis, Nice, 2015. http://www.theses.fr/2015NICE4106.
Full textAbstract:
Les rétrotransposons sont des éléments génétiques mobiles qui constituent presque la moitié de notre génome. Seule la sous-famille L1HS appartenant à la classe des Long Interspersed Element-1(LINE-1 ou L1) a gardé une capacité de mobilité autonome chez l’Homme. Leur mobilisation dans la lignée germinale, mais Aussi dans certains tissus somatiques, contribue à la diversité du génome humain ainsi qu’à certaines maladies comme le cancer. Ainsi, de nouvelles copies de L1 peuvent directement s'intégrer dans des séquences codantes ou régulatrices, et altérer leur fonction. De plus, les séquences L1 contiennent elles-mêmes plusieurs éléments cis-régulateurs et leur insertion à proximité ou dans un gène peut produire des altérations génétiques plus subtiles. Afin d'explorer l'ensemble de ces altérations à l'échelle du génome, nous avons développé un logiciel dédié à l’analyse des données de séquençage d'ARN qui permet d'identifier des transcrits chimériques ou antisens impliquant les L1 et d'annoter ces isoformes en fonction des différents événements d’épissage alternatif subits. Au cours de ce travail, il est apparu que la compréhension du lien entre polymorphisme des insertions et phénotype nécessite une vue complète des différentes copies L1HS présentes chez un individu donné. Afin de disposer d'un catalogue aussi complet que possible de ces polymorphismes identifiés dans des échantillons humains sains ou pathologiques et publiés dans des journaux scientifiques, nous avons développé euL1db, la base de données des insertions de rétrotransposon L1HS chez l’Homme. En conclusion, ce travail aidera à comprendre l’impact des L1 sur l’expression des gènes, à l'échelle du génomeRetrotransposons are mobile genetics elements, which form almost half of our genome. Only the L1HS subfamily of the Long Interspersed Element-1 class (LINE-1 or L1) has retained the ability to jump autonomously in humans. Their mobilization in the germline – but also in some somatic tissues – contributes to human genetic diversity and to diseases, such as cancer. L1 reactivation can be directly mutagenic by disrupting genes or regulatory sequences. In addition, L1 sequences themselves contain many regulatory cis-elements. Thus, L1 insertions near a gene or within intronic sequences can also produce more subtle genic alterations. To explore L1-mediated genic alterations in a genome-wide manner, we have developed a dedicated RNA-seq analysis software able to identify L1 chimeric or antisense transcripts and to annotate these novel isoforms with their associated alternative splicing events. During the course of this work, it appeared that understanding the link between L1HS insertion polymorphisms and phenotype or disease requires a comprehensive view of the different L1HS copies present in a given individual or sample. To provide a comprehensive summary of L1HS insertion polymorphisms identified in healthy or pathological human samples and published in peer-reviewed journals, we developed euL1db, the European database of L1HS retrotransposon insertions in humans. This work will help understanding the overall impact of L1 insertions on gene expression, at a genome-wide scale
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Mir, Ashfaq Ali. "Variations structurales du génome et du transcriptome humains induites par les rétrotransposons LINE-1." Electronic Thesis or Diss., Nice, 2015. http://theses.unice.fr/2015NICE4106.
Full textAbstract:
Les rétrotransposons sont des éléments génétiques mobiles qui constituent presque la moitié de notre génome. Seule la sous-famille L1HS appartenant à la classe des Long Interspersed Element-1(LINE-1 ou L1) a gardé une capacité de mobilité autonome chez l’Homme. Leur mobilisation dans la lignée germinale, mais Aussi dans certains tissus somatiques, contribue à la diversité du génome humain ainsi qu’à certaines maladies comme le cancer. Ainsi, de nouvelles copies de L1 peuvent directement s'intégrer dans des séquences codantes ou régulatrices, et altérer leur fonction. De plus, les séquences L1 contiennent elles-mêmes plusieurs éléments cis-régulateurs et leur insertion à proximité ou dans un gène peut produire des altérations génétiques plus subtiles. Afin d'explorer l'ensemble de ces altérations à l'échelle du génome, nous avons développé un logiciel dédié à l’analyse des données de séquençage d'ARN qui permet d'identifier des transcrits chimériques ou antisens impliquant les L1 et d'annoter ces isoformes en fonction des différents événements d’épissage alternatif subits. Au cours de ce travail, il est apparu que la compréhension du lien entre polymorphisme des insertions et phénotype nécessite une vue complète des différentes copies L1HS présentes chez un individu donné. Afin de disposer d'un catalogue aussi complet que possible de ces polymorphismes identifiés dans des échantillons humains sains ou pathologiques et publiés dans des journaux scientifiques, nous avons développé euL1db, la base de données des insertions de rétrotransposon L1HS chez l’Homme. En conclusion, ce travail aidera à comprendre l’impact des L1 sur l’expression des gènes, à l'échelle du génomeRetrotransposons are mobile genetics elements, which form almost half of our genome. Only the L1HS subfamily of the Long Interspersed Element-1 class (LINE-1 or L1) has retained the ability to jump autonomously in humans. Their mobilization in the germline – but also in some somatic tissues – contributes to human genetic diversity and to diseases, such as cancer. L1 reactivation can be directly mutagenic by disrupting genes or regulatory sequences. In addition, L1 sequences themselves contain many regulatory cis-elements. Thus, L1 insertions near a gene or within intronic sequences can also produce more subtle genic alterations. To explore L1-mediated genic alterations in a genome-wide manner, we have developed a dedicated RNA-seq analysis software able to identify L1 chimeric or antisense transcripts and to annotate these novel isoforms with their associated alternative splicing events. During the course of this work, it appeared that understanding the link between L1HS insertion polymorphisms and phenotype or disease requires a comprehensive view of the different L1HS copies present in a given individual or sample. To provide a comprehensive summary of L1HS insertion polymorphisms identified in healthy or pathological human samples and published in peer-reviewed journals, we developed euL1db, the European database of L1HS retrotransposon insertions in humans. This work will help understanding the overall impact of L1 insertions on gene expression, at a genome-wide scale
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Mittal, Vinay K. "Detection and characterization of gene-fusions in breast and ovarian cancer using high-throughput sequencing." Diss., Georgia Institute of Technology, 2014. http://hdl.handle.net/1853/54014.
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Gene-fusions are a prevalent class of genetic variants that are often employed as cancer biomarkers and therapeutic targets. In recent years, high-throughput sequencing of the cellular genome and transcriptome have emerged as a promising approach for the investigation of gene-fusions at the DNA and RNA level. Although, large volumes of sequencing data and complexity of gene-fusion structures presents unique computational challenges. This dissertation describes research that first addresses the bioinformatics challenges associated with the analysis of the massive volumes of sequencing data by developing bioinformatics pipeline and more applied integrated computational workflows. Application of high-throughput sequencing and the proposed bioinformatics approaches for the breast and ovarian cancer study reveals unexpected complex structures of gene-fusions and their functional significance in the onset and progression of cancer. Integrative analysis of gene-fusions at DNA and RNA level shows the key importance of the regulation of gene-fusion at the transcription level in cancer.
Book chapters on the topic "Chimeric transcripts"
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Chu, Hsueh-Ting. "Transcriptome Sequencing for the Detection of Chimeric Transcripts." In Methods in Molecular Biology, 239–53. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-3204-7_14.
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MacDiarmid, Robin M. "Chimeric, Infectious, and Stable Virus Transcripts to Study RNA Silencing in “Dark Green” Islands." In Methods in Molecular Biology, 299–308. Totowa, NJ: Humana Press, 2012. http://dx.doi.org/10.1007/978-1-61779-882-5_20.
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Huppi, K. "The Generation of Pvt-1/Ck Chimeric Transcripts as an Assay for Chromosomal Translocations in Mouse Plasmacytomas." In Current Topics in Microbiology and Immunology, 399–404. Berlin, Heidelberg: Springer Berlin Heidelberg, 1995. http://dx.doi.org/10.1007/978-3-642-79275-5_46.
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Koller, Barbara, Etienne Roux, Paul-Etienne Montandon, and Erhard Stutz. "A Chimeric Transcript Containing a 16S rRNA and a Potential mRNA in Chloro-Plasts of Euglena Gracilis." In Plant Molecular Biology, 652. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4615-7598-6_86.
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"Chimeric Transcripts." In Encyclopedia of Cancer, 814. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_1097.
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Panovska-Stavridis, Irina. "Molecular Monitoring in Acute Myeloid Leukemia Patients Undergoing Matched Unrelated Donor: Hematopoietic Stem Cell Transplantation." In Acute Leukemias [Working Title]. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.94830.
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Minimal residual disease (MRD) in acute myeloid leukemia (AML) is a complex, multi-modality assessment and much as its clinical implications at different points are extensively studied, it remains even now a challenging area. It is the disease biology that governs the modality of MRD assessment; in patients harboring specific molecular targets, high sensitivity techniques can be applied. In AML patients undergoing allogenic hematopoietic stem cell transplantation (alloHSCT), relapse in considered as leading cause for treatment failure. In post-transplant setting, regular MRD status assessment enables to identify patients at risk of impending relapse when early therapeutic intervention may be beneficent. We analyzed data of AML patients who underwent matched unrelated donor (MUD) HSCT since the introduction of this procedure in the Republic of North Macedonia. Chimeric fusion transcripts were identified in three patients; two of them positive for RUNX-RUNX1T1 transcript and one for CBFB-MYH11. One patient harbored mutation in the transcription factor CCAAT/enhancer binding protein α (CEBPA). Post-transplant MRD kinetics was measured by quantitative polymerase chain or multiplex fluorescent-PCR every three months after the transplantation during the first two years after the transplant. MRD negativity was achieved in three patients by the sixth month of HSCT, who were pre-transplant MRD positive. They sustained hematological and molecular remission for 19, 9 and 7 months, respectively. The forth patient died due to transplant-related complication. Our experience suggests, when molecularly-defined AML patients undergo HSCT, regular MRD monitoring helps predict impending relapse and direct future treatment strategies.
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Oflaz, Ofcan. "Mechanism of HIV-1 Reverse Transcriptase Inhibitors." In Current Researches in Health Sciences-IV. Özgür Yayınları, 2023. http://dx.doi.org/10.58830/ozgur.pub387.c1596.
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The HIV life cycle involves a series of intricate steps: viral entry, reverse transcription, integration into the host genome, transcription and translation, assembly, budding, maturation, and release. The reverse transcriptase (RT) enzyme, a pivotal player in this cycle, facilitates the conversion of viral RNA into double-stranded DNA during reverse transcription. Comprising polymerase and RNase H domains, RT's structure is crucial for its multifunctional role. The polymerase domain synthesizes a complementary DNA strand, while the RNase H domain degrades the RNA template. This enzymatic process results in the formation of a provirus integrated into the host cell's genome. Inhibitors targeting RT, classified into non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs), disrupt this critical step in the HIV life cycle. NNRTIs act allosterically to inhibit RT's activity, while NRTIs function as chain terminators during DNA synthesis, collectively impeding the virus's replication and offering crucial therapeutic interventions in managing HIV infections. Our book chapter covers the fundamental life cycle of HIV, the working mechanism of the RT enzyme, and the effects of inhibitors on this mechanism. The enzyme structure has been visualized using the UCSF Chimera program.
Conference papers on the topic "Chimeric transcripts"
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Jian-lei Gu, Yao Lu, Shi-yi Liu, Cong Liu, and Hui Lu. "A novel scoring estimator to screening for oncogenic chimeric transcripts in cancer transcriptome sequencing." In 2016 IEEE International Conference on Bioinformatics and Biomedicine (BIBM). IEEE, 2016. http://dx.doi.org/10.1109/bibm.2016.7822792.
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Haines, Katherine, Angshumoy Roy, Linghua Wang, Pavel Sumazin, Kyle R. Covington, Donna M. Muzny, Vijetha Kumar, et al. "Abstract A33: Discovery of chimeric transcripts involving APC and TERT in pediatric HCC by RNA sequencing." In Abstracts: AACR Special Conference: Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; November 9-12, 2015; Fort Lauderdale, Florida. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.pedca15-a33.
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Sarver, Nava, and George A. Ricca. "SUSTAINED EXPRESSION OF FULL LENGTH AND VARIANT RECOMBINANT FACTOR VIII IN GENETICALLY ENGINEERED CELLS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643875.
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A major effort is presently underway to provide factor VIII (FVIII) in a form free of viral pathogens via a recombinant DNA approach. We have constructed two chimeric FVIII cDNA vectors based on the bovine papillomavirus mammalian expression system. The first vector (FVIII) contained a full length FVIII cDNA; the second vector (AFVIII) contained a cDNA insert with an extensive deletion, corresponding to amino acid residues 747 to 1560 in the region encoding the "B" domain. This internal region is removed during activation of the parental FVIII molecule and is believed not to be required for coagulant activity. We have found that recombinant FVIII produced by stable cell lines harboring either the full length or the variant FVIII was capable of restoring coagulant activity to FVIII deficient plasma in. vitro. This expressed activity was neutralized by anti-FVIII antibodies. Similar to observations with FVIII derived from human plasma, the two recombinant FVIII forms were (i) inactivated by the chelating agent EDTA, (ii) demonstrated a biphasic response of an initial activation followed by a decay in activity when treated with thrombin, and (iii) presented the expected peptide banding pattern by western blot analyses. A higher percentage of ΔFVIII transformants were isolated expressing coagulant activity compared to transformants harboring the complete FVIII cDNA. Among the positive transformants isolated, those harboring ΔFVIII produced higher levels of coagulant activity than their full length counterparts. Comparable steady state levels of FVIII specific transcripts were detected in FVIII and ΔFVIII transformants indicating that the difference in expression levels is due to a post transcriptional event(s). Our study demonstrates the efficacy of a full length and an abridged recombinant FVIII produced by stably transformed cells in correcting coagulation deficiency in. vitro. It further suggests the potential usefulness of other molecular variants for efficient expression in genetically engineered cells.
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Гордеев, Александр Андреевич, Елена Владимировна Четверина, Марина Витальевна Фалалеева, and Александр Борисович Четверин. "OVERCOMING FALSE POSITIVES OF REVERSE TRANSCRIPTION AT THE DETECTION OF CHIMERIC RNAS." In Высокие технологии и инновации в науке: сборник избранных статей Международной научной конференции (Санкт-Петербург, Январь 2021). Crossref, 2021. http://dx.doi.org/10.37539/vt189.2021.69.97.008.
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Работа посвящена исследованию формирования ложных химерных кДНК в результате смены матриц обратной транскриптазой. Показано, что, изменяя ряд параметров реакции обратной транскрипции, можно существенно уменьшить частоту ложноположительных результатов при выявлении истинных химерных РНК. Полученные результаты позволяют улучшить качество анализа транскриптомов и диагностики заболеваний, ассоциированных с образованием химерных РНК. This work is aimed at the study of formation of false chimeric cDNA as a result of template switch by reverse transcriptase. It is shown that by manipulating a number of parameters of the reverse transcription reaction, it is possible to significantly reduce the frequency of false-positives in the detection of true chimeric RNAs. The results allow to improve the quality of the analysis of transcriptomes and of the diagnostics of diseases associated with the formation of chimeric RNAs.
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Abate, F., A. Acquaviva, E. Ficarra, G. Paciello, E. Macii, A. Ferrarini, M. Delledonne, S. Soverini, and G. Martinelli. "A novel framework for chimeric transcript detection based on accurate gene fusion model." In 2011 IEEE International Conference on Bioinformatics and Biomedicine Workshops (BIBMW). IEEE, 2011. http://dx.doi.org/10.1109/bibmw.2011.6112352.
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Azmi, Muhammad Bilal. "In Silico Basis to Understand the Molecular Interaction of Human NNATGene With Therapeutic Compounds of Anorexia Nervosa." In INTERNATIONAL CONFERENCE ON BIOLOGICAL RESEARCH AND APPLIED SCIENCE. Jinnah University for Women, Karachi,Pakistan, 2022. http://dx.doi.org/10.37962/ibras/2022/1-2.
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Introduction: Anorexia nervosa (AN)– a perplexing heritable, psychiatric eating disorder condition characterized by low body weight. The prevalence of AN is found to be high in younger age adults with a raised mortality rate. Genetic studies have been insufficient in identifying the role of specific genes that predispose an individual to AN. Objectives: The objective was to explore the role of NNAT (neuronatin) gene variants and its structure based molecular interactions with therapeutic compounds of AN. To investigate the role of structural missense pathogenic variants (SNPs: single nucleotide polymorphism) or change in the expression of NNAT with possibility of AN. Methodology: NNAT gene protein coding sequence, SNPs were extracted and validated from public databases. Gene to gene interactions, protein localization and human tissue-specific expression analysis of NNAT gene showed highest tissue-specific expression in the brain. Estimates of functional impact of SNPs using transcript sequence and machine learning based approaches (in silico algorithms) were computed to investigate the pathogenicity and protein stability of NNAT variants. Sequence alignment, ab initio 3D structure-modeling of wild-type, validation and recognition of binding cavities of NNAT through in silico web based tools were performed. Alternate model prediction for NNAT variants through residue specific mutation approach and structural validation were also done through Chimera tool. The 3D compounds involved in the management of AN were extracted from the Drug Bank database, afterwards energy minimization and rule of drug-likeness were performed. The eligible 3D compounds were docked with identified variants, to evaluate the drugs binding molecular mechanics. Results & Conclusion: Overall, 10 NNAT missense variants were extracted on the basis of minor allele frequency (MAF < 0.001) and other consequence types. Further three variants were selected among ten according to the transcript sequence, which includesrs542858994 (F26L), rs539681368 (C30Y) and rs542858994 (F53L). Structures for these variants’ protein were generated, validated and docked with AN drugs. The functional impact analyses of selected missense SNPs of NNAT showed high risk pathogenicity and can cause changes in the physical and chemical properties of amino acids, thus affecting the function of protein. The computation of binding energies of variants of NNAT with AN compounds strengthen the hypothesis that these variants strongly interact with the AN drugs, hence reducing the level of free NNAT as well as target drugs, for neuronal functioning. Therefore, constitutionally reduced level of NNAT and binding of NNAT variants with AN drugs may serve as the basis to increases the susceptibility towards AN.