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Rna splicing

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https://www.readbyqxmd.com/read/29782652/adenosine-methylation-as-a-molecular-imprint-defining-the-fate-of-rna
#1
REVIEW
Philip Knuckles, Marc Bühler
Multiple lines of evidence suggest the RNA modification N6 -methyladonsine (m6 A), which is installed in the nucleus co-transcriptionally and, thereafter, serves as a reversible chemical imprint that influences several steps of mRNA metabolism. This includes but is not limited to RNA folding, splicing, stability, transport, and translation. In this Review we focus on the current view of the nuclear installation of m6 A as well the molecular players involved, the so called m6 A writers. We also explore the effector proteins, or m6 A readers, that decode the imprint in different cellular contexts and compartments, and ultimately, the way the modification influences the lifecycle of an RNA molecule...
May 21, 2018: FEBS Letters
https://www.readbyqxmd.com/read/29782227/cdk5-mediated-acn-acinus-phosphorylation-regulates-basal-autophagy-independently-of-metabolic-stress
#2
Nilay Nandi, Helmut Krämer
In neurons, autophagy counteracts consequences of aging. It is therefore of interest how basal rates of macroautophagy/autophagy can be controlled independently of metabolic stress. We recently investigated the regulation of basal, starvation-independent autophagy by Acn/Acinus, a multifunctional nuclear protein with proposed roles in apoptosis, alternative RNA splicing, and basal autophagy. We found that Acn is stabilized by phosphorylation of the conserved serine 437. The phosphomimetic AcnS437D mutation causes no overt developmental phenotypes, but significantly elevates levels of basal autophagy and extends life spans...
May 21, 2018: Autophagy
https://www.readbyqxmd.com/read/29774215/importance-of-functional-loss-of-fus-in-ftld-als
#3
REVIEW
Shinsuke Ishigaki, Gen Sobue
Fused in sarcoma (FUS) is an RNA binding protein that regulates RNA metabolism including alternative splicing, transcription, and RNA transportation. FUS is genetically and pathologically involved in frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS). Multiple lines of evidence across diverse models suggest that functional loss of FUS can lead to neuronal dysfunction and/or neuronal cell death. Loss of FUS in the nucleus can impair alternative splicing and/or transcription, whereas dysfunction of FUS in the cytoplasm, especially in the dendritic spines of neurons, can cause mRNA destabilization...
2018: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/29774201/investigation-of-experimental-factors-that-underlie-brca1-2-mrna-isoform-expression-variation-recommendations-for-utilizing-targeted-rna-sequencing-to-evaluate-potential-spliceogenic-variants
#4
Vanessa L Lattimore, John F Pearson, Margaret J Currie, Amanda B Spurdle, Bridget A Robinson, Logan C Walker
PCR-based RNA splicing assays are commonly used in diagnostic and research settings to assess the potential effects of variants of uncertain clinical significance in BRCA1 and BRCA2 . The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium completed a multicentre investigation to evaluate differences in assay design and the integrity of published data, raising a number of methodological questions associated with cell culture conditions and PCR-based protocols. We utilized targeted RNA-seq to re-assess BRCA1 and BRCA2 mRNA isoform expression patterns in lymphoblastoid cell lines (LCLs) previously used in the multicentre ENIGMA study...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29773655/foxp3-interacts-with-hnrnp-f-to-modulate-pre-mrna-alternative-splicing
#5
Jianguang Du, Qun Wang, Steven F Ziegler, Baohua Zhou
FOXP3 promotes the development and function of regulatory T cells mainly through regulating the transcription of target genes. RNA alternative splicing has been implicated in wide range of physiological and pathophysiological processes. We report here that FOXP3 associates with Heterogeneous Nuclear Ribonucleoprotein (hnRNP) F through the exon 2 encoded region of FOXP3 and the second quasi-RNA recognition motif (qRRM) of hnRNPF. FOXP3 represses the ability of hnRNPF to bind to its target pre-mRNA and thus modulates RNA alternative splicing...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29771377/alternative-splicing-analysis-in-human-monocytes-and-macrophages-reveals-mbnl1-as-major-regulator
#6
Hongfei Liu, Paolo A Lorenzini, Fan Zhang, Shaohai Xu, Mei Su M Wong, Jie Zheng, Xavier Roca
We report the detailed transcriptomic profiles of human innate myeloid cells using RNA sequencing. Monocytes migrate from blood into infected or wounded tissue to differentiate into macrophages, and control inflammation via phagocytosis or cytokine secretion. We differentiated culture primary monocytes with either GM- or M-CSF to obtain pro- or anti-inflammatory macrophages, and respectively activated them with either LPS/IFNγ or anti-inflammatory cytokines. We also treated the THP-1 monocytic cell line with PMA and similar cytokines to mimic differentiation and activation...
May 16, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29770436/all-i-s-on-the-radar-role-of-adar-in-gene-regulation
#7
REVIEW
Galina Shevchenko, Kevin V Morris
Adenosine to inosine (A-to-I) editing is the most abundant form of RNA modification in mammalian cells, which is catalyzed by adenosine deaminase acting on the double-stranded RNA (ADAR) protein family. A-to-I editing is currently known to be involved in the regulation of the immune system, RNA splicing, protein recoding, microRNA biogenesis, and formation of heterochromatin. Editing occurs within regions of double-stranded RNA, particularly within inverted Alu repeats, and is associated with many diseases including cancer, neurological disorders, and metabolic syndromes...
May 16, 2018: FEBS Letters
https://www.readbyqxmd.com/read/29769602/computational-identification-and-validation-of-alternative-splicing-in-zsf1-rat-rna-seq-data-a-preclinical-model-for-type-2-diabetic-nephropathy
#8
Chi Zhang, Ken Dower, Baohong Zhang, Robert V Martinez, Lih-Ling Lin, Shanrong Zhao
Obese ZSF1 rats exhibit spontaneous time-dependent diabetic nephropathy and are considered to be a highly relevant animal model of progressive human diabetic kidney disease. We previously identified gene expression changes between disease and control animals across six time points from 12 to 41 weeks. In this study, the same data were analysed at the isoform and exon levels to reveal additional disease mechanisms that may be governed by alternative splicing. Our analyses identified alternative splicing patterns in genes that may be implicated in disease pathogenesis (such as Shc1, Serpinc1, Epb4...
May 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29769310/tumor-associated-intronic-editing-of-hnrpll-generates-a-novel-splicing-variant-linked-to-cell-proliferation
#9
Yi-Tung Chen, Ian Yi-Feng Chang, Hsuan Liu, Chung-Pei Ma, Yu-Ping Kuo, Chieh-Tien Shih, Ying-Hsin Shih, Lin Kang, Bertrand Chin-Ming Tan
Processing of the eukaryotic transcriptome is a dynamic regulatory mechanism that confers genetic diversity, and splicing and A-to-I RNA editing are well-characterized examples of such processing. Growing evidence reveals the crosstalk between the splicing and RNA editing, but there is a paucity of substantial evidence for its mechanistic details and contribution in a physiological context. Here, our findings demonstrate that tumor-associated differential RNA editing, in conjunction with splicing machinery, regulates the expression of variants of HNRPLL, a gene encoding splicing factor...
May 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29769303/how-alternative-splicing-affects-membrane-trafficking-dynamics
#10
REVIEW
R Eric Blue, Ennessa G Curry, Nichlas M Engels, Eunice Y Lee, Jimena Giudice
The cell biology field has outstanding working knowledge of the fundamentals of membrane-trafficking pathways, which are of critical importance in health and disease. Current challenges include understanding how trafficking pathways are fine-tuned for specialized tissue functions in vivo and during development. In parallel, the ENCODE project and numerous genetic studies have revealed that alternative splicing regulates gene expression in tissues and throughout development at a post-transcriptional level. This Review summarizes recent discoveries demonstrating that alternative splicing affects tissue specialization and membrane-trafficking proteins during development, and examines how this regulation is altered in human disease...
May 16, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29769273/genome-wide-posttranscriptional-dysregulation-by-micrornas-in-human-asthma-as-revealed-by-frac-seq
#11
Rocio T Martinez-Nunez, Hitasha Rupani, Manuela Platé, Mahesan Niranjan, Rachel C Chambers, Peter H Howarth, Tilman Sanchez-Elsner
MicroRNAs are small noncoding RNAs that inhibit gene expression posttranscriptionally, implicated in virtually all biological processes. Although the effect of individual microRNAs is generally studied, the genome-wide role of multiple microRNAs is less investigated. We assessed paired genome-wide expression of microRNAs with total (cytoplasmic) and translational (polyribosome-bound) mRNA levels employing subcellular fractionation and RNA sequencing (Frac-seq) in human primary bronchoepithelium from healthy controls and severe asthmatics...
May 16, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29769258/anti-tumor-efficacy-of-a-novel-clk-inhibitor-via-targeting-rna-splicing-and-myc-dependent-vulnerability
#12
Kenichi Iwai, Masahiro Yaguchi, Kazuho Nishimura, Yukiko Yamamoto, Toshiya Tamura, Daisuke Nakata, Ryo Dairiki, Yoichi Kawakita, Ryo Mizojiri, Yoshiteru Ito, Moriteru Asano, Hironobu Maezaki, Yusuke Nakayama, Misato Kaishima, Kozo Hayashi, Mika Teratani, Shuichi Miyakawa, Misa Iwatani, Maki Miyamoto, Michael G Klein, Wes Lane, Gyorgy Snell, Richard Tjhen, Xingyue He, Sai Pulukuri, Toshiyuki Nomura
The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025...
May 16, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29768479/construction-of-a-tri-chromatic-reporter-cell-line-for-the-rapid-and-simple-screening-of-splice-switching-oligonucleotides-targeting-dmd-exon-51-using-high-content-screening
#13
Takenori Shimo, Keisuke Tachibana, Satoshi Obika
Splice-switching oligonucleotides (SSOs) that can modulate RNA splicing are used for the treatment of many genetic disorders. To enhance the efficacy of modulating splicing, it is important to optimize SSOs with regard to target sites, GC content, melting temperature (Tm value), chemistries, and lengths. Thus, in vitro assay systems that allow for the rapid and simple screening of SSOs are essential for optimizing SSO design. In this study, we established a novel tri-chromatic reporter cell line for SSO screening...
2018: PloS One
https://www.readbyqxmd.com/read/29768040/myristate-induced-endoplasmic-reticulum-stress-requires-ceramide-synthases-5-6-and-generation-of-c14-ceramide-in-intestinal-epithelial-cells
#14
Songhwa Choi, Justin M Snider, Nicole Olakkengil, Johana M Lambert, Andrea K Anderson, Jessica S Ross-Evans, L Ashley Cowart, Ashley J Snider
Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling...
May 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29767360/transcript-profiling-using-long-read-sequencing-technologies
#15
Anthony Bayega, Yu Chang Wang, Spyros Oikonomopoulos, Haig Djambazian, Somayyeh Fahiminiya, Jiannis Ragoussis
RNA sequencing using next-generation sequencing (NGS, RNA-Seq) technologies is currently the standard approach for gene expression profiling, particularly for large-scale high-throughput studies. NGS technologies comprise short-read RNA-Seq (dominated by Illumina) and long-read RNA-Seq technologies provided by Pacific Bioscience (PacBio) and Oxford Nanopore Technologies (ONT). Although short-read sequencing technologies are the most widely used, long-read technologies are increasingly becoming the standard approach for de novo transcriptome assembly and isoform expression quantification due to the complex nature of the transcriptome which consists of variable lengths of transcripts and multiple alternatively spliced isoforms for most genes...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29765071/effects-of-cold-acclimation-and-dsrna-injections-on-gs1l-gene-splicing-in-drosophila-montana
#16
David Hopkins, Tapio Envall, Noora Poikela, Olli T Pentikäinen, Maaria Kankare
Alternative splicing, in which one gene produce multiple transcripts, may influence how adaptive genes respond to specific environments. A newly produced transcriptome of Drosophila montana shows the Gs1-like (Gs1l) gene to express multiple splice variants and to be down regulated in cold acclimated flies with increased cold tolerance. Gs1l's effect on cold tolerance was further tested by injecting cold acclimated and non-acclimated flies from two distantly located northern and southern fly populations with double stranded RNA (dsRNA) targeting Gs1l...
May 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29764987/rapid-and-dynamic-alternative-splicing-impacts-the-arabidopsis-cold-response-transcriptome
#17
Cristiane P G Calixto, Wenbin Guo, Allan B James, Nikoleta A Tzioutziou, Juan C Entizne, Paige E Panter, Heather Knight, Hugh Nimmo, Runxuan Zhang, John W S Brown
Plants have adapted to tolerate and survive constantly changing environmental conditions by re-programming gene expression. The dynamics of the contribution of alternative splicing (AS) to stress responses are unknown. RNA-sequencing of a time-series of Arabidopsis thaliana plants exposed to cold determines the timing of significant AS changes. This shows a massive and rapid AS response with coincident waves of transcriptional and AS activity occurring in the first few hours of temperature reduction, and further AS throughout the cold...
May 15, 2018: Plant Cell
https://www.readbyqxmd.com/read/29764981/mice-with-endogenous-tdp-43-mutations-exhibit-gain-of-splicing-function-and-characteristics-of-amyotrophic-lateral-sclerosis
#18
Pietro Fratta, Prasanth Sivakumar, Jack Humphrey, Kitty Lo, Thomas Ricketts, Hugo Oliveira, Jose M Brito-Armas, Bernadett Kalmar, Agnieszka Ule, Yichao Yu, Nicol Birsa, Cristian Bodo, Toby Collins, Alexander E Conicella, Alan Mejia Maza, Alessandro Marrero-Gagliardi, Michelle Stewart, Joffrey Mianne, Silvia Corrochano, Warren Emmett, Gemma Codner, Michael Groves, Ryutaro Fukumura, Yoichi Gondo, Mark Lythgoe, Erwin Pauws, Emma Peskett, Philip Stanier, Lydia Teboul, Martina Hallegger, Andrea Calvo, Adriano Chiò, Adrian M Isaacs, Nicolas L Fawzi, Eric Wang, David E Housman, Francisco Baralle, Linda Greensmith, Emanuele Buratti, Vincent Plagnol, Elizabeth Mc Fisher, Abraham Acevedo-Arozena
TDP-43 (encoded by the gene TARDBP ) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects...
May 15, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29764937/cyclin-dependent-kinase-1-cdk1-and-cdk2-have-opposing-roles-in-regulating-interactions-of-splicing-factor-3b1-with-chromatin
#19
Tushar Murthy, Theresa Bluemn, Abhishek Gupta, Michael Reimer, Sridhar Rao, Manoj M Pillai, Alex C Minella
Splicing factor 3B1 (SF3B1) is a core splicing protein that stabilizes the interaction between the U2 snRNA and the branch point in the mRNA target during splicing. SF3B1 is heavily phosphorylated at its N terminus and a substrate of cyclin-dependent kinases (CDKs). Although SF3B1 phosphorylation coincides with splicing catalysis, the functional significance of SF3B1 phosphorylation is largely undefined. Here, we show that SF3B1 phosphorylation follows a dynamic pattern during cell cycle progression that depends on CDK activity...
May 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29759485/roles-of-alternative-rna-splicing-of-the-bif-1-gene-by-srrm4-during-the-development-of-treatment-induced-neuroendocrine-prostate-cancer
#20
Yu Gan, Yinan Li, Zhi Long, Ahn R Lee, Ning Xie, Jessica M Lovnicki, Yuxin Tang, Xiang Chen, Jiaoti Huang, Xuesen Dong
Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that becomes more prevalent when hormonal therapy, chemotherapy, or radiation therapy is applied to patients with metastatic prostate adenocarcinoma (AdPC). How AdPC cells survive these anti-cancer therapies and progress into t-NEPC remains unclear. By comparing the whole transcriptomes between AdPC and t-NEPC, we identified Bif-1, an apoptosis-associated gene, which undergoes alternative RNA splicing in t-NEPC...
May 11, 2018: EBioMedicine
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